Saphnelo vs Benlysta? What is the Best Medicine for Lupus? [FEB 2023 Update]

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Update March 2023:

The journal Lupus reported a study showing that Benlysta is safe and effective to use during pregnancy

Update February 2023:

Benlysta was FDA-approved to treat lupus nephritis in children as young as 5 years old in July 2022!

2023 Benlysta Pregnancy Registry data reported.

Saphnelo is the first lupus drug to prove long-term safety, effectiveness, and steroid-sparing abilities through a randomized, placebo-controlled long term extension trial (a total of 4 years’ of research)

See the results of how patients on Saphnelo do during the COVID-19 pandemic

Benlysta is now regarded as a disease-modifying agent for treating systemic lupus erythematosus (SLE).

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Only two medications (Benlysta and Saphnelo) have been approved by the U.S. Food and Drug Administration (FDA) to treat systemic lupus erythematosus (SLE) since the 1950s. Which is the best medicine for lupus?

Patients often ask me, “between Benlysta and Saphnelo, what is the best medicine for lupus?”

They both have some things in common. They are both biologic drugs (biologics). This means they are produced by expensive living, biologic processes rather than simple chemical-reaction methods. However, most importantly, they were developed specifically to treat parts of the immune system that are particularly overactive in lupus.

Benlysta (belimumab) has been an important standard of care therapy for lupus patients since March 2011.

Saphnelo (anifrolumab) became the second biologic drug FDA-approved to treat systemic lupus erythematosus (SLE) in August 2022: is it the best medicine for lupus, or is Benlysta (belimumab)?

In this blog post, I present the pros and cons of both drugs. Then at the end, I give my opinion on which wins “Best Medicine for Lupus.”

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Other Medicines Used to Treat Lupus

First, I am not saying that either is the best medicine for lupus compared to the other lupus drugs.

Everyone with systemic lupus erythematosus (SLE) should be on an antimalarial (hydroxychloroquine or chloroquine) due to their many benefits and proven long-term safety (as long as you get your two required eye tests yearly).

There is a good reason we call hydroxychloroquine (Plaquenil): “Lupus Life Insurance.” As often said by Dr. Michelle Petri, Chief of the Lupus Center, Johns Hopkins Hospital, “hydroxychloroquine is the only drug proven to prolong survival in lupus patients.”

Also, numerous other immunosuppressants help many patients with systemic lupus erythematosus (SLE) go into remission or low disease activity and lower their doses of steroids (or hopefully get off steroids). Two important goals in treating lupus are achieving remission and having patients off steroids.

The primary advantage of these drugs is that they are less expensive than Saphnelo and Benlysta. A downside is that they require additional labs to monitor their safety.

These other immunosuppressants include steroids (like prednisone), mycophenolate (CellCept, Myfortic), methotrexate, azathioprine (Imuran), and cyclophosphamide (Cytoxan). Throughout this blog post, “the usual lupus drugs” and “other lupus drugs” refer to these immunosuppressants and the antimalarial drugs.

Lupkynis (voclosporin) was the first non-biologic drug FDA-approved for lupus kidney inflammation (lupus nephritis) but is not approved for the treatment of systemic lupus erythematosus (SLE).

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Good Things About Saphnelo

Saphnelo targets one important part of the lupus immune system:

Saphnelo (anifrolumab) is specifically designed to treat lupus by decreasing the effects of a cytokine called interferon type-1. Read my previous article on Saphnelo to learn more.

Saphnelo decreases disease activity in ALL evaluated organ systems:

A measurement was used by Saphnelo called the BICLA (British Isles lupus assessment group-based Composite Lupus Assessment) tool to measure disease activity. This is one of my favorite measurements in lupus research. It is very thorough by evaluating lupus inflammation in ninety-seven different body areas. Saphnelo decreased inflammation in all organ systems that had moderate to severe involvement. It is the only lupus drug to do this. To prove that Saphnelo worked sufficiently on a patient in the research studies (called clinical trials), that patient had to improve in every area moderately or severely affected by lupus. That is impressive!

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In all fairness, the BICLA was not developed until after the Benlysta clinical trials. The BICLA was not measured in the Benlysta research studies. Therefore, it is impossible to say that Saphnelo is better than Benlysta when looking at this measurement.

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Saphnelo works quickly:

Most medicines used to treat lupus are slow to work. However, Saphnelo can work fast. Some patients in the clinical trials had visible improvements after the first dose.

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“Trial” in medicine is used as another word for “research study.” It does not mean trial as used in a legal court situation.

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Saphnelo improves fatigue, intimacy, quality of life, and pain:

These are four of the most common and debilitating problems in systemic lupus erythematosus. Researchers evaluated 360 patients treated with Saphnelo in the phase 3 clinical trials. 54% of Saphnelo patients who met the main target (primary endpoint) of the study had improved energy. This was almost four times as often as the patients who did not respond.

Lupus often interferes with being intimate with one’s partner (due to pain, poor self-esteem, fatigue, loss of sexual desire, etc.). Almost four times as many Saphnelo patients who responded to treatment also had improvements in intimacy compared to those who did not respond. Patients on Saphnelo also had better improvements in numerous other qualities of life and pain measures.

Saphnelo is “steroid-sparing”:

Steroids (like prednisone) are a double-edged sword. They are the only drugs that work immediately, and they can be lifesaving for patients with severe lupus. However, steroids cause side effects in virtually everyone who takes high enough doses and is on them long enough. One goal in treating lupus patients on steroids is to use safer medicines to get them off steroids or at least on lower doses. Rheumatologists call this “steroid-sparing.”

Saphnelo is the only drug to have “steroid-sparing” as a goal (called a “secondary endpoint” ) in the most important research performed (called a phase-3 clinical trial). It reached this goal. 72% more patients treated with Saphnelo plus other lupus drugs reduced their steroids to the target amount compared to lupus patients receiving placebo plus these other lupus drugs.

In other words, patients could lower their steroid doses better when Saphnelo was added to the usual lupus treatments.

Saphnelo decreases lupus flares during steroid tapering

When we lower (taper) steroid doses, trying to get to the lowest amount possible or hopefully off steroids, it is important that patients not flare. Unfortunately, it is common for lupus to flare when steroid doses are lowered. Each lupus flare can cause organ damage, and we do not want that.

Only 20% of patients who received Saphnelo plus other lupus drugs flared during steroid tapering. In contrast, 50% of the patients receiving placebo plus other drugs flared. That is an enormous difference and is an important goal for me.

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Saphnelo is the only lupus drug to prove it improves skin lupus quickly:

Cutaneous (skin) lupus erythematosus (CLE) is a major cause of people with lupus feeling bad due to its ability to cause permanent discoloration of the skin (especially the face) and permanent hair loss (as seen in this photo). Saphnelo is the only drug to evaluate its effects on CLE as an important goal (secondary endpoint) in its most important research study. After just 3 months, at least one out of two patients with CLE had at least a 50% reduction in skin inflammation. This was twice as many patients as those treated with placebo. Anyone who has seen the Saphnelo-treated cutaneous lupus pictures on the internet would be impressed.

Saphnelo is safe in most patients

The number of side effects in the Saphnelo FDA-approved label that occurred in 2% or more of patients, and more often than placebo plus the usual lupus drugs, is quite small. These included allergic reactions, infections, and infusion reactions.

When you look at this list of side effects, two things are important to note—

You want to compare the percentage of those who had that potential side effect on Saphnelo vs. those on placebo. For example, 9.4% of patients treated with Saphnelo had an infusion reaction. Infusion reactions include dizziness, headache, nausea, fatigue, and others. However, 7.1% of patients on placebo (received saline water instead of Saphnelo) had an infusion reaction. This was a small difference. Plus, it shows that simply getting an IV (intravenous, injected into a vein) of anything can make someone feel something.

Also, the clinical trials did not compare Saphnelo to just a placebo. All patients are on medicines that calm down or suppress the immune system (“other lupus drugs”). Therefore, when a patient gets a side effect, one of the other drugs may be the cause. It can be exceedingly difficult to know for sure.

For example, 4.8% of patients on Saphnelo had serious infections while 5.6% of those on placebo did. Does this mean that sugar water causes more infections than Saphnelo? Of course, not. These patients were also on strong immunosuppressants such as mycophenolate and steroids.

Saphnelo does not require any extra labs:

Most of the usual lupus drugs require us to draw blood work (most commonly the blood counts, kidney function, and liver function tests) frequently to monitor the drug and make sure it is not causing side effects. We often have patients come in every 2 to 4 weeks for blood work on these medicines. Saphnelo does not need any extra labs to monitor side effects. Easy-peasy.

Saphnelo does not require premedications:

Many to most IV drugs that we use in rheumatology require us to give our patients steroids, antihistamines, and acetaminophen (Tylenol) before we treat them (called “premedications”). Since Saphnelo rarely causes severe allergic and infusion reactions, patients do not require premedications. This is important because antihistamines and steroids can make people feel bad (drowsy, dizzy, body aches, insomnia, wired, etc.).

Does Saphnelo work better in patients with certain antibodies?

I attended a fascinating lecture by Dr. Mary Crow in November 2021. Dr. Crow is one of the world’s experts on lupus and type-I interferon. She talked about how certain antibodies (anti-Smith, anti-RNP, anti-Ro, anti-SSA, anti-La, anti-SSB) may cause high levels of type-I interferon. She also showed interesting data from her lab (along with Dr. Jing Hua, Dr. M. Olferiev and Dr. K. Kirou). Patients with frequent clinic visits, highly active disease, and high interferon levels tended to have elevated levels of these antibodies. They were less likely to have high anti-dsDNA levels (remarkably interesting).

 She hypothesized that since Saphnelo interferes with type-I interferon levels and activity, it may be especially helpful in patients positive for these antibodies.

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Saphnelo has ground-breaking placebo-controlled long-term study results

As introduced in the graph above, Saphnelo has impressed the rheumatologic community by publishing its 3-year long-term extension study results. A long-term extension trial is a commonly done study where a pharmaceutical company continues to study patients who were in the original research studies that achieved FDA approval (phase-3 clinical trials), then follows them over a longer period of time to ensure the drug is safe and effective over a longer amount of time than just the shorter clinical trials. Most of the time, everyone in the clinical trials is offered the chance to continue into the longer trials, and all patients, including those on placebo, are treated with the actual drug (and not placebo).

However, Saphnelo has truly raised the bar on this type of study. Saphnelo conducted a randomized, placebo-controlled long-term extension study (Kalunian K et al). Half of the patients who were on placebo continued on placebo while the other half were then placed on Saphnelo 300 mg IV monthly (standard dosing). In addition, neither the research doctors nor the patients knew who was on Saphnelo and who was on placebo, allowing an unbiased assessment of how they did on Saphnelo vs placebo. Having a placebo group in a long-term extension trial is amazing (it strengthens the data results).

The patients, by the way, were completely aware they could be on placebo or Saphnelo. Yet, they were not truly on placebo (fake medicine), they still were taking the usual lupus drugs (like hydroxychloroquine, methotrexate, mycophenolate, azathioprine, and steroids).

This helps answer the question: If you add Saphnelo on top of the usual lupus drugs, do more people benefit, can you lower the steroid dose, and is it safe to use over a total of 4 years? (the original study, called the TULIP period, was 1 year, and the long-term extension, LTE, study was an additional 3 years).

You can read the entire paper (linked above) by Dr. Kenneth Kalunian et al above, but here are the bottom lines:

• More patients taking Saphnelo along with other SLE drugs had better disease control
• Patients taking Saphnelo were less likely to have lupus flares
• Saphnelo was safe to take over 4 years
• A big concern regarding side effects was getting shingles. Shingles was much more likely to occur in the first year of treatment. Take away point… make sure patients get at least one Shingrix shot before starting Saphnelo (preferably at least 2 weeks before the first Saphnelo dose).
• Saphnelo allowed a much better reduction in steroids. (see the graph above). At the end of 4 years, three times as many patients taking the “usual lupus drugs” were on more than 7.5 mg a day of prednisone compared to those taking Saphnelo. This is profound. We know that patients taking that much steroids are twice as likely to have ongoing permanent organ damage compared to patients on lower doses.

Does Saphnelo Increase the Risk for COVID-19 Infections and Deaths?

Since Saphnelo interferes with the effectiveness of type-I interferon, and interferon is important in fighting off viral infections, we must wonder if it could potentially increase problems from viral infections like COVID-19. Interestingly, the 3-year long-term extension trial above began on June 30, 2016, and was in full swing when the pandemic hit March 11, 2020. You can see the numbers of COVID-19 infections and deaths in table 4 of the study.

What really sticks out to me in these numbers are the following:

• I am impressed that only 8 patients dropped out of the study because of concerns over the pandemic. That is truly remarkable and shows how dedicated these SLE patients and the researchers were in continuing this important research during a very scary time.
• I am impressed with the low number of infections and deaths over all. Only around 10% of the patients overall became COVID-19 positive, and there were only 3 COVID-19-related deaths. We must remember that the 1st year (before vaccines were available) was a nightmare. I can only assume that the study’s patients may have been more careful than the average person in protecting themselves from COVID-19. That is what I saw in my own SLE patients. Most of my SLE patients were extra vigilant with their social distancing, and when I recommended they be vaccinated, most of them trusted me and did so. And I got vaccinated myself (I do as I preach).
• BOTTOM LINE: The numbers are much too low to draw any conclusions as to whether Saphnelo may increase the risk of COVID-19 or not. However, it is interesting that the vast majority of COVID infections and all 3 deaths occurred before the time when vaccines became available in December 2020. My take away from this is (just as I recommend to all my SLE patients) … keep up on your COVID-19 vaccines and continue to protect yourself, continue social distancing, and ask all loved ones also to vaccinate themselves so you can take advantage of the “cocoon effect.” I’ve seen many patients get very sick; I’ve unfortunately had patients die … but these problems are markedly less common in those who are extra careful and who do as recommended.

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Could Saphnelo be the best medicine for lupus with all these positive benefits, or is it Benlysta with all of its positive benefits? Read on…

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Down Sides of Saphnelo

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Saphnelo is new: what happens in the long run?

This is always a concern about new drugs. However, we do have data on Saphnelo safety and efficacy from monitoring research patients over 3 years. While the original studies (clinical trials) only lasted 1 year, many patients continued Saphnelo and participated in “long-term extension” trials.

The patients in the 3-year long-term extension trial continued to have superior results from Saphnelo without increased side effects. Only 7% of patients stopped Saphnelo due to side effects. Saphnelo decreased lupus inflammation, but it also improved quality of life.

Saphnelo increases the risk of shingles

Shingles is a very painful rash due to the chickenpox virus. People with systemic lupus erythematosus (SLE) are already three times more likely to get shingles than older healthy people.

The vast majority of those treated with Saphnelo did not get shingles. However, five times more Saphnelo patients got shingles than those treated with placebo.

I recommend that all my patients get a shingles vaccine (preferably Shingrix) before starting Saphnelo. The Shingrix vaccine is 95% effective at preventing shingles.

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Saphnelo can only be given by IV

Medical professionals (usually nurses) give Saphnelo intravenously (IV) by infusing it into a vein. The patient usually needs to go to an infusion center every 4 weeks to get Saphnelo. It can be difficult for someone with a busy lifestyle (work, family) to carve out time for a monthly infusion.

Saphnelo has not been studied in severe lupus nephritis or CNS lupus:

People with severe kidney inflammation (lupus nephritis) or severe involvement of the brain or spinal cord (CNS lupus) were not studied in the clinical trials. Therefore, we do not know if it works for them. This is contrary to Benlysta, which helps severe lupus nephritis.

However, patients with less severe lupus nephritis were allowed in the Saphnelo clinical trials (as long as their serum creatinine was less than 2.0 mg/dL, urine protein was less than 2 grams per 24 hours, and they did not require pulse IV steroids or cyclophosphamide).

Patients with CNS lupus could also participate as long as they did not require pulse IV steroids or cyclophosphamide.

Saphnelo should not be used during pregnancy or breastfeeding:

Saphnelo has not been studied in pregnant or breastfeeding women and is too new of a drug to know if it is safe or not in these situations.

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Biologics (Saphnelo and Benlysta) are much more expensive than most SLE drugs

Both drugs are much more expensive than the “usual lupus drugs.” For example, a year’s supply of hydroxychloroquine costs anywhere from $292 to $3175 per year. A standard mycophenolate (CellCept) dose costs $396 to $8760 per year. Saphnelo and Benlysta cost in the tens of thousands of US dollars a year.

I obtained the above “average wholesale prices” on UpToDate (and goodrx.com) in June 2022.

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Good Things about Benlysta

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Benlysta targets one important part of the lupus immune system:

Like Saphnelo, Benlysta (belimumab) targets one overactive section of the immune system in lupus. Lupus experts designed Benlysta specifically for lupus. Read my previous blog post on this topic of how Benlysta works.

Since Benlysta and Saphnelo each target a different area of the lupus overactive immune system, each may work better in some patients than in others. See below where I discuss how I plan on using Benlysta and Saphnelo in different types of lupus patients.

Benlysta satisfied one of the hardest research lupus goals:

All three pivotal phase III clinical trials used the SRI-4 (SLE Responder Index-4) as their main research goal (called the primary endpoint). Each clinical trial evaluated every lupus patient at the end of the research study to see if they met the SRI-4 goal. An SRI-4 result had to include all three of the following:

• The research doctor had to determine there was no disease worsening.
• The person could not have had any severe flare during the study or more than one moderate flare.
• The person had to decrease their SLEDAI (SLE Disease Activity Index) score by 4 points or more; hence the “4” in SRI-4. (In reality, they used a version called SELENA-SLEDAI, but I do not want to get too technical).

Reducing the SLEDAI score by four points is difficult as the SLEDAI scoring system is virtually close to an “all or nothing” approach. For example, if someone had a lupus rash (2 points), all rash inflammation had to be completely gone at the end of the study to count for a 2-point reduction.

In the Saphnelo studies, a significant improvement in the rash would count for the BICLA score (discussed above); it did not have to resolve as it does in the SRI-4 used for Benlysta.

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Note that the BICLA and the SRI-4 have their pros and cons. Neither system is proven to be a better research goal than the other (though I lean more towards liking the BICLA since it is more sensitive to improvements in disease activity than SRI-4, and it looks at many more lupus problems than the SRI-4 does).

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Benlysta is safe and effective when taken for a long time:

Studies have been conducted with Benlysta in patients taking it for as long as 13 years over which time it was safe and effective. No drug has been formally tested so stringently, in so many people, over such a long period of time as Benlysta has. It i has met its primary end points (main goal of the study) in more research studies than any other SLE drug, repeatedly proving its effectiveness and safety when assessing a large number of SLE patients.

Quality of life improves with Benlysta:

Just like Saphnelo, Benlysta improved the quality of life. Approximately twice as many patients on Benlysta (plus the usual lupus drugs) ended up with a better quality of life than those on placebo plus the usual lupus drugs.

Benlysta is a steroid-sparing drug:

As discussed above with Saphnelo, Benlysta is also a steroid-sparing drug. Benlysta did not have a “steroid-sparing effect” as a secondary endpoint (as Saphnelo had). However, in over five studies, Benlysta lowered steroid doses in lupus patients. Therefore, Benlysta is a steroid-sparing drug.

This does not necessarily mean that Saphnelo results in greater steroid reductions than Benlysta. The Benlysta research studies did not include enough patients on steroids to prove this in just one study. However, it did when looking at multiple studies.

Benlysta decreases lupus flares:

The three main phase 3 clinical trials for Benlysta showed that it decreases lupus flares. There was a 43% reduction in severe flares in the BLISS-52 study and a 49% reduction in the BLISS-SC study. Both were statistically significant. The BLISS-76 study had a numerical difference in reducing severe flares, but it did not reach statistical significance.

Benlysta is FDA-approved for lupus nephritis:

Lupus attacks the kidneys (lupus nephritis) in approximately 40% of systemic lupus patients and is a major cause of doing badly from lupus.

Benlysta made history in December 2020 by becoming the first (and only) biologic FDA-approved to treat lupus nephritis. Patients with lupus nephritis had a 74% greater odds of having a complete renal response (remission or close to remission) when Benlysta was added to mycophenolate or cyclophosphamide plus steroids than patients treated with standard therapy (mycophenolate or cyclophosphamide plus steroids without Benlysta).

Benlysta is the only FDA-approved for children with systemic lupus and lupus nephritis:

Unfortunately, children get SLE. Children and teenagers tend to have more severe lupus than older people with SLE. 20% of SLE adults developed lupus when they were children or teenagers. Therefore, we need more FDA-approved drugs for juvenile-onset lupus.

In 2019, Benlysta again made history by becoming the only drug FDA-approved to treat children as young as 5 years old with systemic lupus erythematosus using the IV form.

Lupus nephritis (kidney inflammation) affects most pediatric SLE patients and is a major cause of their not doing well. Fortunately, Benlysta was proven to work better for pediatric lupus nephritis patients when added to older drugs compared to using the older drugs by themselves. Therefore, in July 2022, the FDA-approved IV Benlysta for children (as young as 5 years old) with lupus nephritis. This truly is a remarkable achievement for our pediatric population who suffer from such severe disease.

Benlysta is a disease-modifying agent for systemic lupus and lupus nephritis:

In 2022, Dr. Urowitz et al published a paper showing significant reductions in organ damage, including kidney damage, in lupus patients using Benlysta long term. The authors made the conclusion that this means Benlysta can be a disease-modifying agent for lupus. The only other drug that can truly claim this title is hydroxychloroquine. This is one of the best pieces of news we have heard in a long time and can be a reason to consider using Benlysta over Saphnelo.

Patients taking Benlysta plus the usual lupus drugs were 60% less likely to have ongoing organ damage each year during a 7-year study period than patients taking the usual lupus drugs (without Benlysta). This is excellent news. I have many patients on Benlysta who are doing very well and off steroids because of Benlysta. When they ask me if they can stop Benlysta or not, I point out this study.

I always like to put myself in a patient’s place when I give them advice. If I had systemic lupus erythematosus (SLE) and was doing well on Benlysta plus hydroxychloroquine, I would continue Benlysta with hydroxychloroquine to prevent organ damage.

Benlysta is safe in most patients:

The list of potential side effects from Benlysta is relatively short, as noted in the chart in the FDA-approved label showing those side effects that occurred in at least 3% of patients taking Benlysta plus the usual lupus drugs and occurred at least 1% more frequently than placebo plus the usual lupus drugs.

Important caveats are similar, as noted above in the Saphnelo section regarding the importance of realizing that all patients were on drugs other than Benlysta and placebo. For example, 0.7% of patients taking Benlysta stopped it because of infections, while 1.0% of those on placebo did. This does not mean that placebo caused more infections resulting in drug discontinuation. These patients were on other immunosuppressant drugs.

Remarkably, there were few side effects when one thinks about it.

Benlysta does not require any extra labs:

Like Saphnelo, Benlysta does not need additional labs to monitor side effects.

Benlysta does not require premedications:

Life Saphnelo, the IV form of Benlysta does not require the use of premedications.

Benlysta can be taken by IV or by self-injection:

Like Saphnelo, Benlysta comes in an IV monthly form. However, patients can also inject it underneath the skin (subcutaneous, SC or SQ) at home. Patients inject Benlysta under the skin once weekly and is easy.

People who prefer that a professional (usually a nurse) administer the drug often choose the IV (intravenous) form over the SQ form.

Benlysta has proven itself to be safe and effective in the most clinical trials:

Proving that a drug works for lupus is extremely hard since every lupus patient is different. Most drugs studied for lupus fail to prove they work. Benlysta reached its main goal (called a primary endpoint) in all three phase-III clinical trials (BLISS-52, BLISS-76, and BLISS-SC). Benlysta has achieved its primary endpoint in more phase 3 clinical trials than any lupus drug. It has also been formally studied in more lupus patients than any other drug. These are amazing feats!

Benlysta has subsequently shown to be safe and effective in eight clinical trials! A very nice summary of these Benlysta research studies is in the journal “Lupus.”

Benlysta especially helps patients with severe disease, low complements, and high anti-dsDNA:

Identifying what patients may respond best to a drug is an important goal. We usually have to use “trial and error” in most lupus patients, trying different medicines until we find the best for one patient. Doctors and patients often have to try multiple drugs until they find the best combination. Not only can this be very expensive (up to tens of thousands of wasted dollars), but it results in undue patient suffering and a feeling of failure by the doctor who is trying their best to help the patient.

The Benlysta EMBRACE trial showed that patients with low C3, low C4, or a high anti-dsDNA level tended to be most likely to respond. Also, patients with the most severe disease tended to be more likely to respond than patients with milder disease.

When I have a lupus patient with severe fatigue, arthritis pain, and other lupus problems, if they also have these lab abnormalities, I usually recommend trying Benlysta. Most patients in this situation usually do much better, achieving more energy and less arthritis pain.

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Benlysta Shown to be Safe and Effective During Pregnancy

Benlysta was shown to be safe and effective during pregnancy in a March 2023 study and after an evaluation of the Benlysta Pregnancy Registry.

• Women who took Benlysta during pregnancy numerically had similar live birth rates compared to women who stopped their Benlysta.
• No lupus flares occurred in the women who took Benlysta, while four women who stopped Benlysta had lupus flares during pregnancy.

Note, this opinion is based upon the science and has not been formally accepted into the 2020 American College of Rheumatology Reproductive Guidelines. However, these guidelines were formulated before this data was available. When these Guidelines are updated, I’d be very surprised if Benlysta is not included among the list of safe drugs during pregnancy.

About the Pregnancy Registry and Original Clinical Trials (BLISS-52, BLISS-72)

The Benlysta FDA-approved label recommends not taking it during pregnancy or breastfeeding because it was not studied formally in the clinical trials. Note that even if it becomes included in the list of safe drugs for pregnancy per the ACR Reproductive Guidelines, the label will most likely remain the same since pregnancy was not studied in the clinical trials.

An ongoing pregnancy registry has kept track of pregnant Benlysta patients. Around the Spring of each year, the results are typically made public on how patients on Benlysta do when they get pregnant.

Biologics, like Benlysta, are large molecules. They do not cross the placenta and go into the fetus very much in the first two trimesters. Research shows that some biologics appear safe during the 1^st two trimesters. On the other hand, undertreated, active lupus inflammation is dangerous for the baby and mother.

For a nice summary of pregnancy registry data of Benlysta in lupus patients, see the 2023 analysis by Dr. Michelle Petri, et al.

Benlysta and Breastfeeding

Benlysta molecules are large, and minuscule amounts enter breast milk. There are studies suggesting that biologics are safe during breastfeeding. Suppose a lupus patient wanted to breastfeed and needed to be on Benlysta. In that case, I would most likely prescribe it if she understands that it has not been formally studied and is “off label.”

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Benlysta costs less than Saphnelo

As discussed above in detail, both the SQ and IV forms of Benlysta cost less than Saphnelo (unless the intravenous form is given to someone weighing around 215 pounds or more).

Down Sides of Benlysta

Benlysta’s Package Insert warns about depression and suicidality:

The two intravenous phase-3 clinical trials (BLISS-52 and BLISS-76) and a study called the BASE (Belimumab for Adults with active SLE) trial had an increased number of depression and suicidality events. The differences between Benlysta and placebo were not statistically significant, but there were numerical differences. One person committed suicide and they were taking Benlysta.

Interestingly, the BLISS-SC phase 3 clinical trial (using self-injectable Benlysta) did not increase depression or suicidality. However, people with major psychiatric problems did not participate in the research study.

Are depression and suicidality true side effects? In my using Benlysta in many patients since 2011, I have had only one patient stop Benlysta for this possibility. If it does, it is a very uncommon side effect.

If you are on Benlysta and have a history of major psychiatric issues, let your doctor know if you become more depressed.

Benlysta has not been studied in severe CNS lupus:

As with Saphnelo, people with severe CNS (brain and spinal cord) lupus did not participate in the clinical trials. Therefore, we do not know how they will do when treated with Benlysta.

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How about Benlysta in African Americans?

Many African Americans have been hesitant about using Benlysta for their SLE. This is partly due to the FDA requiring the following statement on the Benlysta package insert: “In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies. Use with caution in black/African-American patients.]”

• The belimumab phase 2 clinical trial actually did show that belimumab worked in the African American population. However, it is data from phase 3 clinical trials that are used to report drug effectiveness by the FDA.
• In the phase 3 clinical trials, only around 10% of all patients were of African descent. This is a markedly lower number of black patients than we see in the US. In fact, most of my SLE patients are of African descent. Reasons why there were so few is that many of the research centers were in Europe, Asia, and South America (where the number of black patients is much less than in the US). In addition, the recruitment of African Americans in the US was difficult.
• Due to the above, there were too few African-descent patients to reach “statistical significance.” An example of how this works is, let’s say you do a study searching for how often a penny comes up heads or tails. You flip it twice; both times, it comes up heads. You cannot say that when flipping a penny, 100% of the time, it will come up heads. It is easy and logical to understand this. This is a very basic example of a study not reaching statistical significance. A statistician can calculate how many times the coin must be flipped to obtain a correct answer. This is what happened in the Benlysta studies. There were fewer people of African descent than needed to get a correct answer.
• Since then, we do have evidence that it works well in African Americans:
  • Most of my SLE patients are of African descent. I have quite a few who have been on Benlysta since it first came out 11 years ago and are doing fantastic on it… many are in remission or low disease activity, and almost all are off steroids (or on very low doses).
  • I hear the same from my peers at major medical centers.
  • In 2016, a multicenter study was published showing that Benlysta worked in African American patients treated for two years. It also showed steroid-sparing efficacy. At the start of the study, the average prednisone dose was 20 mg a day (much too high and dangerous). After two years, the average dose was down to 6 mg a day.
  • Last year, 2022, the results of the EMBRACE trial (Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus) were published. Again, it was difficult to recruit African Americans into the study (a recurrent problem in the US). However, 448 patients did participate. Although there were not enough patients to reach statistical difference, it showed effectiveness and safety in African Americans.
  • I am convinced that Benlysta works in patients of African ancestry. What we do know, is that patients who tend to do best on Benlysta is the group of patients who either have high disease activity, low C3, low C4, or high anti-dsDNA. I have also found it very helpful in patients with high EC4d levels. Nonetheless, many patients in the clinical trials with moderate disease (instead of high disease activity) and who did not have these abnormal labs responded well to Benlysta. In other words, all groups of patients appeared to respond, but those in those groups (severe disease and abnormal labs) had a higher response rate. This also proved true in the EMBRACE trial, in African American patients.
  • Bottom Line: I tell patients to ignore the caution on the package label. It was included due to there not being enough patients in the FDA-assessed studies.

WHAT IS THE BEST MEDICINE FOR LUPUS?

In my opinion, they are both a “Best Medicine for Lupus.”

When added to the usual lupus drugs, they lower disease activity, pain, and fatigue, while improving quality of life. They also are well tolerated by most patients with few major side effects.

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HOW I PLAN ON USING BENLYSTA AND SAPHNELO

I currently have thirteen lupus patients who failed most lupus drugs, and I have been waiting for Saphnelo to come along. Though Benlysta worked very well in most of my patients, all these patients had failed Benlysta. So, bottom line, I am currently using it in my Benlysta failures.

As discussed above, I have seen fantastic results with Benlysta in my patients who have high anti-dsDNA, low C3, low C4, and high EC4d. This includes patients who have disabling fatigue as a part of their lupus. So, I will lean towards recommending Benlysta for patients with these lab results (called “positive serologies” by lupologists).

As mentioned above, Dr. Mary Crow theorizes that patients with Smith, RNP, Ro, SSA, La, or SSB antibodies may especially respond well to Saphnelo. (This is a theory and not a proven point.) Suppose I have a patient with these antibodies and active lupus while having normal serologies (C3, C4, EC4d, and anti-dsDNA). In that case, I may steer the patient towards Saphnelo.

However, I always leave the decision up to the patient. Suppose an SLE patient requires something in addition to their hydroxychloroquine to control their lupus better. In that case, I discuss the options: mycophenolate, methotrexate, azathioprine, Benlysta, and now Saphnelo. I present the pros and cons and leave it up to the patient.

After presenting the above facts, it is not surprising that most of my patients have chosen Benlysta in the past. Most of them have been incredibly happy with their choice, and most were able to come off their steroids due to Benlysta. It is one of the few drugs to help my patients’ fatigue.

Some results with Saphnelo

So far, I have seen three of my patients back in the clinic who I treated with Saphnelo (and had failed Benlysta). They are doing fantastic. All three had cutaneous lupus that resolved completely (one with discoid, one with vasculitis and subacute cutaneous lupus, and one with mouth ulcers and sun-sensitive rashes). Their fatigue and joint pains were either gone or much better, and these results occurred quickly (most after the first dose of Saphnelo).

However, insurance companies rule the world of medicine. With Benlysta being cheaper, I wonder if they will prefer Benlysta over Saphnelo. On the other hand, pharmaceutical companies often make exclusive deals with insurance companies and offer their drugs at a reduced price. Saphnelo could be the preferred drug for some insurance companies if this occurs.

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SUMMARY OF PROS AND CONS

Shared Pros of Saphnelo and Benlysta:

• They target one part of the immune system important in lupus
• They were both designed specifically for lupus
• They are steroid–sparing drugs
• They reduce lupus flares
• They are generally safe
• They do not require additional monitoring labs
• Premedications are not needed for the IV forms

Pro with some similarities between Saphnelo and Benlysta:

• They both met their main research study goals (called the primary endpoints in the phase-3 clinical trials)
  • Saphnelo had to improve all organ systems with moderate to severe inflammation (part of the BICLA)
  • Benlysta had to achieve complete (to near-complete) resolution of organ system involvement of at least a 4-point reduction in the SELENA-SLEDAI score (part of the SRI-4)
• Both drugs improve quality of life, decrease pain, and improve energy
• They both showed excellent safety, effectiveness, and steroid-sparing abilities in their long term extension trials.

Pros of Saphnelo only:

• Saphnelo works fast, often after the first dose
• Saphnelo is proven to reduce cutaneous lupus quickly
• Saphnelo improves intimacy
• Saphnelo is the only drug to ever use a randomized, placebo-controlled methodology for its long-term extension trial in lupus; proving it is safe and effective over a long period of time using a placebo group.

Pros of Benlysta only:

• Benlysta has 13 years of safety and efficacy data
• Benlysta has been shown to be a disease-modifying agent
• Benlysta is the only FDA-approved biologic for lupus nephritis
• Benlysta (IV form) is the only drug FDA-approved drug for children with lupus
• Benlysta-treated patients had less organ damage over 7 years than patients on the usual lupus drugs
• Benlysta can be self-administered at home
• Benlysta has been studied in more clinical trials and patients than any other lupus drug
• Benlysta especially works well in those with low complements, high anti-dsDNA, or high disease activity (targeting these patients could lessen the “trial and error” approach)
• Benlysta has been shown to be safe and effective during pregnancy. In Dr. Thomas’ opinion (as well as those who participated in the research study), Benlysta should be part of the safe drug list during pregnancy.

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Shared Con of Saphnelo and Benlysta:

Both should not be used for severe CNS lupus

Cons with some similarities between Saphnelo and Benlysta:

• Neither is recommended during pregnancy or breastfeeding
  • However, the Benlysta Pregnancy Registry results (and data on other biologics) suggest it may be safe in the first two trimesters
• Neither is recommended during breastfeeding
  • However, insignificant amounts of Benlysta enter breast milk. It may be safe during breastfeeding.
• Theoretically, the above also probably applies to Saphnelo (since it is a large molecule). However, it is too new for me to recommend its use during pregnancy and breastfeeding

Saphnelo only cons:

• Saphnelo is new
• Saphnelo increases shingles 5-fold (get a Shingrix shot beforehand)
• Saphnelo is only available in IV form (less convenient)
• Saphnelo has not been studied in severe lupus nephritis
• Saphnelo is more expensive than Benlysta

Benlysta only cons:

• Benlysta may increase the risk of depression and suicidality (but this is not a proven side effect)

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THE BOTTOM LINE:

Both drugs are fantastic choices for lupus patients, and both are a candidate for “Best Medicine for Lupus.” The future is becoming brighter and brighter for patients suffering from lupus.

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Author:

Donald Thomas, MD, author of The Lupus Encyclopedia

Have you been treated with Benlysta or Saphnelo?

How have you done on it?

Please comment at the bottom of the page if you can think of any pros and cons I may have missed.

Please type your experience in the comments section.

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To learn all about Saphnelo in detail, read my previous post.

Read about Benlysta here.

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Disclosures

Dr. Thomas is on the Speakers’ Bureaus of GSK (producer of Benlysta) and AstraZeneca (producer of Saphnelo). The views expressed in this blog post are solely my own. I am not writing this post as an agent or representative of GSK or AstraZeneca.

Do not accept this information as direct medical advice. Only your doctor can help you decide the best treatments for your condition.

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erratum

1. This erratum note aims to correct an error in the calculation of pricing comparisons between Benlysta and Saphnelo in my original post.

The information in UpToDate for Saphnelo reads “300mg/2mL (per mL): $2760.33”

I made the mistake of not realizing this was being listed as only one unit (one mL) of Saphnelo rather than the full dose (which is two units, or 2 mL), which would be a price of $5520.66 instead of $2760 (a gross undercalculation of the cost).

This error is corrected in this post as of 6/9/22.

2. My interpretation of the quality of life data on Saphnelo was not correct in my original post. I corrected it on 6/24/22.

DONALD THOMAS, MD, 6/9/22