The Tale of Two TULIPs

When bringing a medicine from concept to reality, success is never promised. More certain are the costs: effort, money, and time (measured in years). One recent success story – AstraZeneca’s Saphnelo (anifrolumab) – was decades in the making, but could now make a real difference to the lives of patients living with systemic lupus erythematosus (SLE), a notoriously difficult-to-treat disease.

One of the key players in anifrolumab’s story is Richard Furie, Chief of the Division of Rheumatology, Director of the Program in Novel Therapeutics at Northwell Health, and a globally recognized authority on lupus treatments. Here, Furie takes us on journey – from inception to FDA approval.

Who does lupus affect – and how?

Lupus is an autoimmune disease, which puts it in the same camp as rheumatoid arthritis, Sjogren’s syndrome, and inflammatory bowel disease (IBD) – to name but a few. In such diseases, the immune system goes haywire and starts attacking the body. The element that differentiates each autoimmune disease is the target for attack. In Inflammatory Bowel Disease, it’s the gastrointestinal tract; in rheumatoid arthritis, it’s mainly the joints. Lupus can attack any part of the body, but the most common manifestations are arthritis, rash, and kidney disease. 

As for the pathogenesis of lupus, there certainly appears to be some genetic susceptibility, with scientists constantly finding new genes (I believe the count now sits at over 100). But there also seems to be an environmental trigger. Scientists have been looking at the viral causation of lupus for decades, and we now know that ultraviolet light can trigger the disease, or at least make it worse for patients. We know that another trigger for some patients is smoking. But, in truth, we simply do not have it all fully figured out.

There was a very famous study done in the early 2000s; researchers examined a serum bank in the US military, identified patients with lupus, and then examined the patients’ blood from years before. From that study, the researchers were able to identify certain antibodies that we now associate with lupus. Their findings align with current thinking: lupus begins as a susceptibility, and then there is a trigger that causes people to start producing antibodies typical of autoimmune disease. Over time, a threshold is crossed, and one develops clinical aspects of lupus.

Within the US, the disease varies greatly. According to current classification criteria, just over 200,000 people in this country have lupus, though that number may be higher. Of that number, roughly half will at some point experience kidney involvement. The two most common manifestations of lupus are skin rash and joint pain.

As to the question of who gets lupus, there is a 10:1 ratio of female to male patients. The disease also disproportionately affects certain racial (Black and Asian) and ethnic (Hispanic) groups in terms of incidence and severity.

Since symptoms are so varied, what are the challenges when defining treatment options?

We rheumatologists are somewhat old-fashioned – we evaluate patients by actually talking to them (I sometimes think this is a lost art). We talk to them, examine them, and perform blood tests. The next order of business is to make a list of the various manifestations of the disease, and prioritize the symptoms from most to least severe. This is really where the art of rheumatology steps in, as opposed to a clearly defined algorithm. The doctor needs to figure out which medicine is best for the patient – not only which medicine, but also what dose. It is hard to answer any general question about treatments without pointing to specific manifestations.

The reality is that many drugs used to treat lupus do not address the underlying drivers of the disease. While commonly prescribed therapies, such as oral corticosteroids, have been effective in managing symptoms for patients, they also contribute to organ damage when taken long term, and when considering that lupus as a disease also damages the organs, you can see how this starts to become a real problem for our patients who require long-term treatment. 

I should also mention that, when we talk about damage, we're not only talking about damage from the disease itself; we’re also talking about the damage that develops as a result of being on medication. We rheumatologists (and patients) have a love-hate relationship with steroids. They’ve been transformative for all of the inflammatory diseases we deal with, but they also cause many side effects. The same goes for immunosuppressives. These drugs are, in a sense, another source of damage that we need to mitigate.

What is the story behind Saphnelo?

In some ways, our story begins in London in 1957, when two investigators made an interesting discovery (1). They had taken influenza virus, heat-inactivated it, and put it into a live chicken egg. Next, they challenged the chicken egg with a live influenza virus, but the live influenza virus wouldn’t grow! Long story short, the cells in the chicken egg were producing a protein that interfered with viral replication. The investigators called it “viral interference,” later shortening it to “interferon.” For the next few decades, interferon was known as a protein that helped with host defence against viral infections.

In 1979, a group from the US National Institutes of Health published the results of a survey of various rheumatic disease patients, screening for interferons in their blood (2). They found that about 71 percent of patients with active SLE, and 21 percent of patients with inactive disease, had interferon in their blood. The researchers concluded that, besides protecting against viral infections, interferon could have something to do with lupus.

In the early 1990s, case reports emerged about cancer patients who were treated with interferons (3,4). Here, investigators found that some of the patients treated with interferons developed a lupus-like illness. A decade later, in the early 2000s, papers were published that discussed the interferon gene signature (5,6). Interferons are very hard to quantify, but one can measure their presence by studying the genes that they activate. Known as the interferon gene signature, this represented a technological advance – a way to facilitate research and survey patients to determine whether their interferon pathway was activated. Once armed with this technology, the burning clinical question was: does interferon play a role in lupus pathogenesis?

The answer: yes. The next natural question became: Can we inhibit interferon pathway activation in lupus patients to reduce disease activity? And that’s when drug development started.

A few companies developed antibodies against one particular subtype of type I interferon, alpha interferon, that inhibited the interferon gene signature, but the first two attempts were not really successful – in fact, one was an outright failure. We needed to improve upon our ability to inhibit this pathway.

Now, we need to get into the nitty gritty of the biology of anifrolumab. To reiterate a very important concept, prior attempts to neutralize interferon targeted one particular interferon molecule: interferon alpha. But there are other types of interferon, including beta, omega, and two others. Anifrolumab blocks the receptor that all 5 type I interferon subtypes bind to – and so we saw a greater inhibition of the interferon gene signature in patients with activated pathways who received anifrolumab in contrast to those who received the more selective alpha interferon antibody. 

Phase I with anifrolumab was performed in scleroderma – a different disease in which the interferon pathway is active. Our first foray into lupus was with the phase IIb “MUSE” study, and the results were phenomenal – the best results I had ever seen in a lupus clinical trial. The study served as the foundation for the phase III program, which consisted of TULIP-1 and TULIP-2.

TULIP-1 studied two different doses compared with standard of care, and TULIP-2 studied one dose compared with standard of care – both global studies enrolling patients with active lupus. While seeking patients for these studies, we cast a wide net; after all, lupus is the most heterogeneous disease there is. Sure enough, some patients came in with rash, some had arthritis, and others came in with a range of other symptoms.

Barring a couple of differences, the two TULIP studies were similarly designed at the outset. One had three arms, and the other had two. TULIP-1 enrolled slightly faster than TULIP-2, so its results were available sooner.

And... TULIP-1 failed! It was a huge shock that it did not reach the endpoint of a statistically significant reduction in disease activity in patients with moderate-to-severe SLE, as measured by the SLE Responder Index (SRI).

However, another endpoint measured in lupus trials, including in the TULIP studies, is known as the British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA). Anifrolumab performed well with this endpoint in TULIP-1, which was not so surprising as it performed quite well in the phase II study. The real surprise was the outcome of the SRI in TULIP-1. Why did one work, and not the other? And what did this mean for TULIP-2?

Following a great deal of discussion with experts, we changed TULIP-2’s endpoint from SRI to BICLA; however, TULIP-2 succeeded in both SRI and BICLA. Then we started looking at other secondary endpoints, such as flare rates, effect on arthritis, effect on skin disease, and the ability to taper steroids. All in all, the totality of the data between MUSE, TULIP-1 and TULIP-2 pointed to a very successful drug.

The big risk was: how would regulators react to the failed TULIP-1 study? Well, in the end, the FDA looked at the totality of the data and were confident enough to approve the drug for SLE in August 2021.

How do you see Saphnelo impacting the SLE treatment landscape?

The drug is very new, but time will tell. Rheumatologists are very astute observers – and they'll use it as appropriate. For example, one aspect that has stood out since phase II is the drug’s effect on skin disease, which makes biologic sense because there is a lot of interferon in the skin of lupus patients.

I believe that rheumatologists will probably eventually turn to anifrolumab for skin disease. The data also shows additional benefits for other manifestations, such as arthritis, prevention of flare, and ability to taper steroids. The name of the game in lupus is to prevent damage, because the accumulation of damage contributes to mortality. To do this, we have to start from the beginning and reduce disease activity.

Is it difficult to get patients to enrol on lupus trials?

It is hard to find patients with disease that is active enough. If a patient has too little disease activity to qualify – or if they barely squeak over the line – they may not prove to be a very informative case, because such patients are allowed to stay on their background therapies. We don’t want a high placebo response rate, but when symptoms are mild and easy to treat, the placebo response rate will be high. Therefore, we need patients with very active disease.

Another factor to consider is the diversity of patients’ motivations. Everybody has a different opinion about participating; some are eager to participate for their own benefit; some are eager to participate because they have colleagues, friends, or relatives with the disease; others don’t want to participate at all because they’re concerned and afraid. This is a problem because, right now, there is unprecedented activity in the field, and we need all the participants we can get.

How can pharma companies encourage more participation in studies?

Well, patients need to know about the studies. In my experience, pharma companies often have little-to-no contact with patients due to ethical and legal considerations, so the contact must come through physicians.

Here is an interesting question (to which I do not have an answer): What percentage of lupus patients are taken care of by rheumatologists with a special interest in lupus and lupus investigation? Because this subset of physicians would be prime candidates for study investigators. Therefore, we need to find out who cares for the lupus population, and we also need to find new ways to reach that population. 

Years ago, the Lupus Foundation of America was awarded a grant, and we proposed a mechanism through the black churches of America. It was a novel way to reach and inform patients, and I think we need more programs like this. 

Overall, there have been enormous struggles in the lupus field. We started our venture in lupus drug development in the early 1990s. At that time, it was failure after failure after failure. We struggled for what felt like a century, but we’re now starting to see some drug approvals, which will no doubt lead to better outcomes for our patients. More drug approvals can come – but we have to get the lupus community involved. We have to get patients participating in trials.

Are you working on any other projects related to lupus?

AstraZeneca’s anifrolumab is being investigated for lupus nephritis (LN), a severe form of lupus affecting the kidneys, with data presented at a major conference in June 2021. The study did not hit the primary endpoint, but there were encouraging results in a group that received a higher dose that led investigators to conclude further investigation was warranted. One of the problems with LN is that patients undergo protein loss in their kidneys, which means they clear the drug a little faster. In short, we may just have to give them more.

AstraZeneca is now turning its attention to a phase III trial anifrolumab for lupus nephritis and a separate phase III trial looking at a subcutaneous preparation.

Now that the drug is approved, we can focus on more aspects of lupus (cutaneous lupus erythematosus, or lupus affecting the skin), and other diseases where there is interferon pathway activation, such as scleroderma, myositis, and Sjogren’s syndrome. Even outside of rheumatology, there is evidence of interferon pathway activation in other illnesses, such as diabetes, tuberculosis, HIV, and cardiac disease. 

And so the anifrolumab journey is far from over; rather, one could say it is just beginning...