A Popular Cancer Target Is Eyed for a Rare Immune Disorder

November 19, 2021

PI3K inhibitors have been an area of great interest for drug developers targeting cancers, but they’ve been difficult to turn into promising drugs due to safety concerns and a lack of efficacy in clinical trials. Pharming, though, believes PI3K can be a valuable target to treat APDS, a rare, immune condition. The company is working to develop Leniolisib, which it licensed from the drug giant Novartis in 2019. We spoke to Anurag Relan, chief medical officer of Pharming, about APDS, the role its PI3K inhibitors can play in treating the condition, and why these drugs may have broader use in autoimmune and inflammatory diseases.


Daniel Levine: Anurag. Thanks for joining us.

Anurag Relan: Thanks Danny for having me.

Daniel Levine: We’re going to talk about Pharming, the ultra-rare disease APDS, and your efforts to develop a treatment for it. Perhaps we can start with APDS for listeners not familiar with the condition. What is it?

Anurag Relan: Yeah, so APDS stands for activated PI3K delta syndrome. It’s a relatively new disease that’s only been fully characterized in the last 10 years or so, and it’s a primary immune regulatory disorder. What that means is that it’s a genetic disease that involves both a deficiency of the immune system, which leads to problems such as frequent infections, and it also has a dysregulatory component on the immune system. So, there’s problems with autoimmunity and what we call lymphoproliferation, which is abnormal proliferation of lymphocytes, or B and T cells. The disease itself can vary widely from person to person so it’s quite heterogeneous in terms of its clinical presentation, but in general, it’s a progressive disease that can lead to end organ damage, and sometimes even malignancy, such as lymphoma.

Daniel Levine: How does the condition manifest itself in progress?

Anurag Relan: It’s interesting because like a lot of primary immune deficiencies it’s quite heterogeneous in the symptoms that patients have, but there’s typically a few major categories of symptoms. The first, because it is a primary immune deficiency and these are really hallmark symptoms that these patients have, is that they get recurrent infections. The most common infections are recurrent sinus infections, ear infections, and then infections in the lungs such as pneumonia. These infections can be difficult to treat and sometimes recur on a repeated basis. And then on top of these types of bacterial infections, these patients are also prone to what’s called herpes virus infections, such as Epstein-Barr virus and cytomegalovirus CMV, which are seen in about half of patients as well. So, on the one end, we have these recurrent infections.

On another key feature of the disease is, what I mentioned earlier, lymphoma proliferation and this is really another hallmark of the condition. What this means is that in these patients, lymphocytes proliferate and grow abnormally. So clinically what we see is swollen lymph nodes or lymphadenopothy, we can also see this as a swollen spleen or liver, and then in the airway or in the gut, this is called a lymphoid hyperplasia where you get these nodules of immune cells that can contribute to poor airway function, cause problems within the GI tract, cause problems such as chronic malabsorption, and just overall inflammation in the bowels. All of these things, especially things such as malabsorption, can cause a lot of problems, especially in children, such as failure to thrive. So, we have infections, we have lymphoproliferation and I think the third big piece or the third feature of the disease is autoimmunity. So not only is the immune system not working properly and able to fight off infections and proliferating in an abnormal way, but it’s also attacking the body. Most commonly what we see here are autoimmune cytopenia. So, we see low blood counts and that can cause a lot of other issues for these patients. Those are probably the three big areas in terms of how we could define the disease: repeated infections, lymphoproliferation, and autoimmunity. We do see other features and as we’re learning more and more about the disease, we see some patients have asthma. We see there’s a subgroup of patients that have a neurodevelopmental delay, and we’re trying to understand how this is occurring, whether this is part of the actual process itself or the disease process itself, or if this is secondary to some of these other things that are going on. And what we also know is that some patients will have some or all of these conditions, but they can also evolve over time.

So, it is quite heterogeneous. The disease itself, and I should also mention, is a genetic disease. So the symptoms begin early in life, but oftentimes these patients may not receive a specific diagnosis until later in life. For example, adults who have the condition, since it was only characterized in 2013, may not be characterized. I mean, may not actually be diagnosed until much later in life. And as with most rare diseases, there is a diagnostic delay. So these patients oftentimes go for years without receiving a specific diagnosis. We do have a website that we’ve created now, called “allaboutapds.com,” for patients as well as healthcare providers to review these clinical manifestations and other aspects of APDS to really educate the community about the condition.

Daniel Levine: At a biological level, is it understood what’s happening to the B cells?

Anurag Relan: Well, the condition itself is caused by overactivity in this enzyme, phosphoinositide-3-kinase delta or PI3K delta. This enzyme plays a key role in the development and function of B and T cells in the immune system. In order for these cells to mature and work properly, there needs to be balanced signaling of this enzyme and this pathway, and it needs to be turned on and turned off at precisely the right moments. So, patients who have APDS or who have a mutation in one of two genes that encode these different sub units of the enzyme, they end up with a hyperactive PI3K delta pathway. And because this pathway is not balanced anymore, these patients have low numbers of functional immune cells that fight off infection and have an excess of immature immune cells that lead to these other problems that we discussed in terms of the immune dysregulation. It’s also hypothesized that this pathway may be involved in cells in the nervous system. And that could explain some of the other phenomena that we see in patients.

Daniel Levine: Did I understand you to say it’s considered a genetic disease?

Anurag Relan: It is a genetic disease and the cause is fairly well understood in terms of these two genes that lead to these problems. There’s basically variants in these two genes that can lead to hyperactivity of this enzyme. For most patients what that means is, because it’s a genetic disease, they would have received a bad copy from one of their parents. Now there are also what’s called spontaneous cases or de novo cases. These are patients who have the condition without a family history, but for the most part, this is a disease that’s passed from parent to child.

Daniel Levine: How has the condition generally diagnosed and how difficult is it to diagnose?

Anurag Relan: It is a difficult condition to diagnose. It’s one of those conditions that’s difficult because it has so many different manifestations and oftentimes patients are diagnosed with broader conditions. So they may be diagnosed simply with primary immune deficiency, or what’s called a combined immune deficiency or another category called common variable immune deficiency. Sometimes patients are only diagnosed when they develop a lymphoma. Because of these different manifestations, because it’s a rare condition, because it’s only been recently described, it is a difficult condition to diagnose. That said, things are changing and things are really improving because of the availability of genetic testing and genetic testing is really the only way to make any definitive diagnosis of APDS. Genetic testing has become more widely available in the last three or four years. So even though the condition has been described for several years longer, it’s only the last couple of years where genetic testing is now available.

In addition to genetic testing, healthcare providers may become suspicious of APDS when they see certain clinical manifestations or laboratory results. So, we’ve talked about the clinical manifestations, but some of the laboratory results that sometimes are seen in these patients, we see low levels of immune globulin, and specifically IgG. But on the other hand, you see high levels of IgM. So, when you see this pattern, it can raise some suspicion about the condition. In terms of clinical manifestation, the combination of immune deficiency, as well as autoimmunity together, as well as in the presence of these swollen lymph nodes or large spleen, this can be a red flag. Obviously, a family history of primary immune deficiency would be a big red flag. But eventually these things all lead to a suspicion and ultimately the provider needs to perform a genetic test to confirm and make the accurate diagnosis of APDS.

Now, I mentioned that the genetics has become more widely available in the last several years, and we’ve actually partnered with a genetic testing company called Invitae to offer no charge genetic testing to include actually a full panel of more than 400 genes that are involved in primary immune deficiency. This test is now available through this program that we have developed. We have more details about the program, including some genetic counseling that we offer to patients, pre and post-test. For more information, you can see this at navigateapds.com. I think a big area of focus for us is to educate providers about the availability of testing and the need for testing, especially when you see these certain clinical manifestations of autoimmunity, recurrent infections, and lymphoproliferation because what we’re hearing from patients and those people that have been diagnosed and doctors who’ve been involved in these patients’ care is that these patients often see numerous doctors. They’ve seen, of course, their primary care doctors, pediatricians, oftentimes they’ll see hematologists, a gastroenterologist, and because of the recurrent lung infections they’ll be seen by pulmonary physicians.

This is certainly a challenge for these patients and quite frustrating that they’re hopping around from doctor to doctor partially because of our fractured healthcare system that doesn’t allow for this interdisciplinary communication. Oftentimes these patients do end up with an immunologist who can see that they have a problem related to their immune system based on some of the laboratory testing and hopefully get a genetic test to make a confirmed diagnosis. A lot of our efforts are around the concept of educating, not only these immunologists about the availability of testing, but also these other sub-specialists who may be seeing these patients but not recognizing that the symptoms that they’re having are part of a larger disease complex, a syndrome where there’s numerous manifestations. The goal is that eventually with the widespread availability of genetic testing with education, that we can reduce this diagnostic delay and prevent some of the progression of the disease that can be associated with APDS and even prevent some of these patients, hopefully, from developing lymphoma, which is obviously quite serious, right?

Daniel Levine: How are patients with the condition generally treated today and what’s their prognosis?

Anurag Relan: It’s a complicated situation because on the one hand, there’s this diagnostic delay of sometimes up to 10 years for these patients to get a correct diagnosis and when they do get a diagnosis, the treatment options are limited. There are no approved, targeted therapies that are trying to normalize, let’s say, the abnormal enzyme that’s hyperactive in these patients. So, the PI3K delta enzymes—there’s nothing targeting that that’s approved currently. So basically what clinicians are left with are trying to treat the manifestations. If they’re getting recurrent infections, then you give them antibiotics. Oftentimes these patients are also placed on immune globulin replacement therapy. But then, if they get problems with autoimmunity, they’re placed on immunosuppressants to try to combat that aspect of the disease. So it’s really a complicated picture. And the care for these patients is really a delicate balancing act between trying to manage the immune deficiency as well as the dysregulation at the same time sometimes in these patients.

Like I said, the challenge is getting that specific diagnosis because these patients are often admitted to the hospital. They’ll sometimes have repeated surgical procedures, get their tonsils out, their spleen removed, numerous biopsies of their lymph nodes, sometimes even bone marrow biopsies. And as you can imagine, given those issues in terms of not having a correct diagnosis, super imposed with these limited treatment options, that really does impact the quality of life that these patients have. They frequently miss school, work, you know, mental health issues are a serious problem. What we’re finding though, is that getting a diagnosis, even in the absence of a treatment today can be quite helpful because now the provider can manage the condition better, being aware of what the prognosis is, what to look for, what to be aware of in terms of the development of lymphoma. But obviously the goal is to develop a specific therapy that can help these patients in a more targeted manner.

Daniel Levine: You’ve in-licensed, a PI3K inhibitor from Novartis. This is a class of drugs that have been largely pursued as treatments for cancer. These drugs have been difficult to develop for cancer. Why have they been so problematic?

Anurag Relan: That’s also a difficult question to answer. I think there’s probably at least two factors that are relevant. The first is that, as you mentioned, this class of drugs have been tried primarily in oncology and they’ve been tried for various refractory cancers. There’s a complex biology involved in a number of these cancers, and I think the other aspect here is that the numerous inhibitors that have been tried, let’s say they’re really the first generation of inhibitors. And a lot of them also had different selectivity for the different forms or isoforms of the PI3K enzyme complex. So, what we’re seeing is that it’s a very complicated situation where you had numerous drugs that are associated with different toxicities and different tolerability issues in the setting of these various cancers.

What we’re seeing now, in terms of the work that Novartis has done in developing this PI3K delta inhibitor—the first aspect to note is that this is really a second-generation inhibitor. It’s also focused on this delta isoform of the enzyme. So that’s one thing to note. The second is that we’re dealing with a different patient population here. These patients with APDS have a hyperactive PI3K delta pathway because of that genetic mutation, that pathway is hyperactive, and there is imbalanced signaling in this pathway leading to those issues that I mentioned earlier with the immune system, development and the manifestation or the maturation of the immune system and the B and T cells in this setting.

What we’re talking about here is trying to normalize and return these patients to a balance pathway. So, in a sense, it’s actually much more straightforward trying to match this drug to the disease because you have this hyperactive enzyme and you’re trying to normalize that as opposed to the complex milieu that you might have in oncology, where there’s numerous other things going on. I think in that combination of using a second-generation drug with more isoform selectivity, as well as focusing in these patients where there’s a clear mechanism of disease that’s related to this PI3K pathway hyperactivity, I think the hope is that the drug will be able to address these patients’ underlying cause in a more direct and better tolerated manner.

Daniel Levine: And what is the drug you’ve in-licensed and what’s the case for using it in an APDS?

Anurag Relan: Yeah, the name of the drug is leniolisib. It’s an orally bioavailable, PI3K delta inhibitor. The structure is significantly different from those first-generation inhibitors that have been developed for oncology primarily, and this may improve the tolerability. That remains to be seen, but that is the goal—to improve the tolerability. The basic mechanism is really trying to normalize these patients and return to balance signaling in this PI3K pathway. I think we have a good understanding of that pathway, and we’re going to have a good understanding of how the two genes involved in APDS lead to hyperactivity in this pathway. Since the root cause is this hyperactivity and we have a targeted PI3K delta inhibitor in leniolisib, we think we have a good basis to try to address this root cause.

Daniel Levine: What is the relationship with Novartis going forward? Did you just in-license the drug or are you actually working with them in any capacity?

Anurag Relan: We are closely working with them. They were responsible for finishing the phase 2/3 study, and that study completed enrollment earlier this year. We are in the process of getting that study wrapped up and hope to have data from that study early in 2022. Per the licensing terms, Pharming will then take over the full responsibilities of the program and be responsible for regulatory submissions as well as further clinical development. So, we’re in close partnership with them there and look forward to continuing to work with them in this manner.

Daniel Levine: Well, what’s not about leniolisib from studies that have been performed to date?

Anurag Relan: So, Novartis conducted a two-part phase 2/3 study, using leniolisib. Part 1 was an open label dose escalation study to assess the safety, tolerability, PKPD, in six patients with APDS and those results have been published in the journal Blood. Those results were then used to determine the optimal dose in the double-blind placebo-controlled part of the study, Part 2, with an additional approximately 30 patients. This study, which is still wrapping up, is designed to assess the safety as well as efficacy of the drug. The primary endpoints of the study are looking at changes in the B-cell profile specifically, trying to determine how many naïve, out of total B cells, are developing, and secondly to look at lymphoproliferation. So, looking at the size of the lymph nodes and how those change over time, under either placebo or with the drug. Part 2 of the study completed enrollment in June of this year and we expect that the results from that study will be available early in 2022. In addition, there is an ongoing open-label extension study to allow patients who were in that part to study to roll over to receive leniolisib on a longer-term basis to collect additional safety and efficacy data.

Daniel Levine: What’s the path forward? What would it take to get to a regulatory filing for approval?

Anurag Relan: The goal is first to review the data that we receive in the beginning of 2022 and if all goes well, to file both with FDA and EMA in 2022, and hopefully even have a regulatory approval, before the end of 2022.

Daniel Levine: Pharming’s not alone in looking at PI3K inhibitors to treat immune disorders. Are you looking at all beyond APDS?

Anurag Relan: We are and we’re going to look at this very carefully in a scientifically driven manner, really looking at what the unmet needs are in various conditions. I think our focus right now is around APDS and getting the results analyzed and discussing the path forward with FDA and EMA, as well as other regulatory agencies across the world to see if a leniolisib would be a suitable treatment for APDS, but we are definitely going to be looking at other immune disorders where there may be an opportunity to use a drug such as the leniolisib.

Daniel Levine: And how does leniolisib figure into Pharming’s broader pipeline?

Anurag Relan: Pharming has been focused on the field of immunology for quite a number of years, decades. In fact, we have, one product on the market called Ruconest. It’s a recombinant human C1 inhibitor for the treatment of acute attacks of hereditary angioedema, which is another rare disease involving the complement and contact cascades of the immune system. In addition to that, we have a new partnership with Orchard Therapeutics to develop a gene therapy for HAE. Really the work that we’re doing now with APDS, and leniolisib is an extension and focus of our work in the field of immunology. So, I think the work with leniolisib fits in quite nicely with this pipeline.

Daniel Levine: Anurag Relan, chief medical officer of Pharming. Anurag, thanks for your time today.

Anurag Relan: Really appreciate the time Dan and speaking to you about APDS. Thank you.

This transcript has been edited for clarity and readability.


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