Drugs to Watch: What are the drivers and barriers for future blockbusters? – transcript

Mike Ward:  Hello. My name is Mike Ward, and welcome to Conversations in Healthcare, a broadcast series brought to you by Clarivate. In this episode, we’re going to be highlighting the recent publication of our Drugs to Watch in 2021 report. And I’m delighted to be joined by one of the lead authors Joan Tur, who is a competitive analyst here at Clarivate.

Joan, first, can I ask you actually how the candidates selected by Clarivate colleagues were picked as Drugs to Watch?

Joan Tur: Sure. First, thanks for having me, Mike. It’s great to be here. Drugs to Watch identifies drugs entering the market or launching key indications with the potential to become blockbusters within five years. As our listeners will know, the blockbuster status is a milestone that means that the drug achieves over $1 billion in annual sales. So analysts at Clarivate leveraged data from various solutions, including Clarivate drug, disease landscape and forecast reports as well as Cortellis sales data sourced from Refinitiv IBES.

So each candidate is researched and evaluated in its individual context, analyzing its strengths and weaknesses, focusing on clinical data, regulatory status, patents, deals and so on. The disease landscapes for each candidate are also examined from all angles, including competition from other therapies, treatment algorithms, disease epidemiology and pricing strategies.

So what’s the result? In 2021, Drugs to Watch highlights four brands. These include Biogen and Eisai’s aducanumab, which is seeking approval for Alzheimer’s disease; UCB Pharma’s bimekizumab, for plaque psoriasis; Takeda’s Relugolix, already approved for uterine fibroids in Japan, prostate cancer in the US and in development for endometriosis pain; and finally Bayer and Merck’s vericiguat, which is marketed in the US as Verquvo in heart failure patients with reduced ejection fraction.

Mike Ward: Probably the most controversial pick by the team is Aducanumab, which is that beta-amyloid-targeting monoclonal antibody that has been developed by Biogen and Eisai, which if approved would be the first disease modifying therapy for Alzheimer’s patients.

I spoke to Jon Searles, who is a senior director of CNS/ophthalmology therapy at team Clarivate, who shared his thoughts on the evidence provided from the Phase Ib trial PRIME trial and two Phase III trials ENGAGE and EMERGE that might support the approval of aducanumab.

Jon Searles: It is the detailed results of these three trials that comprise the principal evidence base for the regulatory submission packages that have been submitted in multiple countries in the world in the past nine months. Stepping back for a second, the approval of aducanumab would be, obviously as you mentioned in your intro, sort of a watershed moment in AD and a major clinical, and commercial, and regulatory milestone. The drug’s efficacy is not overwhelming, and there’s clear evidence, or clear room I should say, for improvement for more effective DMTs down the line, either as monotherapies or in synergistic, multimodal combinations to maximize outcomes. But experts do consider the benefits of the drug as demonstrated to be clinically meaningful, and the approval of the drug would by definition be a groundbreaking start in an area that has seen 100% pipeline attrition for decades.

Mike Ward: While Jon noted that clinicians believe that there is evidence that Aducanumab could be meaningful for patients, I was wondering, Joan, what do you think might be the biggest barriers to this candidate actually being a successful drug?

Joan Tur: If despite some of the doubts surrounding its efficacy, aducanumab gets approved, it will indeed be a game-changer, radically transforming the Alzheimer’s disease market by becoming the first disease-modifying therapy, in a large population where only symptomatic therapies are available.

There are however some disease-modifying therapies in clinical development that could compete with aducanumab in the future. This includes some beta-amyloid agents, which is the same target as Aducanumab, which are in phase two and three legal development. And these include another molecule also being developed by Eisai and Biogen, which is called Lecanemab, which would be injected bi-weekly by intravenous injection.

Then there is one component being developed by Roche called gantenerumab, which is expected to be dosed monthly by injection, which would have a pretty good advantage compared to the intravenous injection of Aducanumab. And another beta-amyloid drug in development is one being developed by Eli Lilly called donanemab.

In addition to drugs targeting beta-amyloid, there are also drugs that are targeting other mechanisms of action, such as the case of Tau. There have been some recent disappointments, like a drug being developed by Roche called semorinemab, failing in the phase II trial. But there are also some therapies that are being developed that also show some promise. So there’s that. There’s some promise for therapies that are already in the pipeline that could compete, some disease-modifying agents, against aducanumab.

Mike Ward: Most of the drugs that have historically featured as a Drug to Watch, tend to be first in class candidates targeting previously untreatable conditions. However, one of the Drugs to Watch in 2021 picks is Bimekizumab, which is a humanized monoclonal antibody targeting both IL-17A and IL-17F, that’s been developed by UCB as a treatment for psoriasis.

Given that the treatment options for psoriasis already represent a crowded market, I asked Mohit Nasa, who is a manager of the immune and inflammatory disorder biopharma insights team at Clarivate to explain why Bimekizumab actually qualifies as a Drug to Watch.

Mohit Nasa: So there’s always a need for better treatments especially for chronic diseases and psoriasis is no different. So based on the data so far Bimekizumab has successfully proven itself better than many efficacious drugs already on the market. In different clinical studies Bimekizumab has proven that it is superior to ustekinumab, which is an IL-17 inhibitor and adalimumab which is a TNF alpha inhibitor and secukinumab which is another IL-17 inhibitor. Scientifically what sets Bimekizumab apart from rest of the IL-17 inhibitors is its effectiveness in blocking IL-17A and IL-17F while the rest of the IL-17 inhibitors, but only work on IL-17A cytokine.

Mike Ward: So, Joan, if Bimekizumab looks like it might be more efficacious and has a better safety profile than other treatments, what barriers will it need to overcome for it to emerge as a genuine blockbuster medicine?

Joan Tur: Its drawback, despite having superior efficacy to the standard of care, including the TNF-alpha inhibitor Humira and the IL-23 inhibitor Stelara, bimekizumab is still a late entrant to the very crowded and competitive market of psoriasis, with almost 11 biologic compounds currently being marketed for the indication.

Also Bimekizumab is initially expected to be used as a third or fourth line of treatment. So it will have to achieve the preferred inhibitor status to advance in earlier lines.

And also Bimekizumab would particularly face stiff competition from the best in class IL-23 inhibitor, Skyrizi, which has also shown impressive efficacy in non-related conditions for which Bimekizumab is in co-development, such as psoriatic arthritis. So that could be one of their fiercest competitors.

Mike Ward: Launching in an already crowded market is also going to be a challenge for our third pick as a Drug to Watch. Vericiguat is a novel oral soluble guanylate cyclase stimulator that’s been developed by Bayer and Merck and was approved in early 2021 by the FDA as a treatment of heart failure with reduced ejection fraction. Reflecting on vericiguat’s entry into a crowded and competitive market that is also populated by generic medicines, here is Dominika Rudnicka-Noulin, who is a senior business insights analyst in the Cardiovascular, Metabolic, Renal and Hematological disorders team at Clarivate.

Dominika Rudnicka-Noulin: So it is true that the heart failure market has been highly genericized, and many of the main standard of care treatments have been available for years and even decades, but it is important to mention that even though a number of effective treatments exist, patients with chronic heart failure and heart failure with reduced ejection fraction continue to experience high rates of mortality and morbidity. So there is definitely room for improvement.

Nearly 30% of patients with HFREF, heart failure with reduced ejection fraction, require re-hospitalization within three months. And especially patients with worsening heart failure are at highest risk of re-hospitalization and mortality. And up-to-date treatments targeting specifically these sub-populations have been lacking.

So vericiguat is a welcome addition to the treatment armamentarium of heart failure with reduced ejection fraction, as it demonstrated it can further improve patient outcomes when used in combination or on top of standard of care treatment in this high-risk population.

And it’s important to remember that heart failure is one of the most prevalent cardiovascular diseases, and it’s the most common reason for hospitalization of patients over 65 years of age. So again, vericiguat, with its ability to reduce heart failure hospitalizations, is an attractive treatment option.

Mike Ward: So Joan, Dominika noted that vericiguat will be a welcome addition to the treatment armamentarium of heart failure with reduced ejection fraction. How will it be differentiated from other treatment options, and which patients are most likely to benefit?

Joan Tur: Good question. The heart failure market is indeed a crowded one, and it’s highly genericized. However, it is the first drug specifically approved in a specific subpopulation of heart failure patients–those with reduced ejection fraction–which are a highly underserved population that continues to experience high rates of mortality and morbidity. And often requires hospitalization despite current treatments. So there’s still a high unmet need in these patients.

So the current standard of care is Entresto from Novartis. But because vericiguat has a different mechanism of action, being a guanylate cyclase stimulator, this is also an advantage. Meaning that vericiguat can be used in combination with the standard of care.

All in all, vericiguat is a highly welcome addition to the heart failure armamentarium, as you say, because it’s able to find the niche in this high-risk population of heart failure patients, and it’s a very welcome addition to the available drugs.

Mike Ward: Often drugs that achieve blockbuster sales do so because they’re effective and used in different indications. And it’s for this reason that relugolix, a gonadotropin-releasing hormone antagonist, is on this year’s Drug to Watch 2021 list.

It’s already been approved in Japan to treat uterine fibroids, and in the United States as a prostate cancer treatment. And it’s also in development as a potential treatment of endometriosis-related pain.

To discuss the drug’s potential. In three indications, I was joined by Raina Priyadarshini, a senior business analyst in the infectious and rare diseases team at Clarivate, and Caroline do Pazo, a business insights analyst on the oncology team at Clarivate.

While it has the potential in all three indications, the biggest driver for relugolix to achieve blockbuster status is actually in the uterine fibroids.

Raina Priyadarshini: The target population for uterine fibroids is huge. It’s estimated that almost 25% of women of reproductive age have fibroids at some point in their life. It’s one of the leading causes why women have to get hysterectomies in the United States. The current therapy which are out there, they all suffer from one or the other causes, and everything has almost a suboptimal efficacy which leads to patients having to resort to only the invasive surgical options, or maybe a minimally invasive option such as endometrial ablation. But nothing that is out there which really provides a disease modifying therapy for the patients.

Mike Ward: Joan, while there is a clear medical need, other drug classes such as GnRH agonist or progesterone receptor modulators are already available. So how might relugolix compete with these?

Joan Tur: Good question, Mike. It’s true that hormonal contraceptives are the first line of treatment, and are inexpensive, but the problem is that they are largely ineffective. The same way the GnRH agonists. They are widely used, and actually are widely generic now. But the problem with this is that they are associated with menopause-like symptoms, such as hot flashes, headache, and nausea.

So relugolix also has the advantage versus these GnRH agonists such as Lupron of being an oral therapy, which is very convenient. And also by being dosed more frequently than Lupron, it improves their ability to manage potential menopause-like symptoms by modifying the doses more easily.

Mike Ward: It is a similar situation in prostate cancer, an indication which relugolix was approved in the United States at the end of 2020, because there are also alternative treatment options, including other GnRH antagonists and agonists. However, Carolina was clear to explain why relugolix might be able to compete.

Carolina do Pazo: I think the main difference between relugolix and the alternative treatments that we have available in prostate cancer as you mentioned, the GnRH agonist and the antagonist that is approved, is that relugolix is an oral medication, while all the other treatments are administered by injection. And I think the great advantage of relugolix can be seen very clearly when we compare it with degarelix which is the other GnRH antagonist in the market because this agent–degarelix– is given us as a subcutaneous injection every four weeks. And the problem that it has is that it produces a lot of local side effects at the site of injection such as pain, inflammation, and sometimes fever. So I think it’s a great opportunity, and a great benefit also for the patients to have another option of treatment and not have to go through every month with these local side effects that the injection produces.

And then I think another great advantage of relugolix is related to its safety profile. So relugolix was evaluated in the phase III HERO trial against leuprolide, which is a very popular GnRH agonist in the prostate cancer market. And actually relugolix was associated with a lower risk of major adverse cardiovascular events compared to leuprolide.

Mike Ward: Joan, so physician’s anxiety about increased risk of cardiovascular events associated with GnRH agonist is what will potentially drive up use of relugolix in prostate cancer?

Joan Tur: Yes, this is indeed one of the major advantages of relugolix over GnRH agonists, and ts it has much lower risk of cardiovascular events. And this will increase its use particularly in patients that are maybe at higher risk of cardiovascular events.

Also another advantage versus GnRH agonists, particularly Lupron, is that they act by initially raising testosterone levels and causing a clinical flare. Relugolix, on the other hand, is associated with a rapid decrease in testosterone, which is likely to enable rapid testosterone recovery when the treatment ends. Which is a very strong opportunity for the drug.

Mike Ward: The third indication that relugolix has been lined up for is in endometriosis-related to pain, a condition for which the first-line therapies are hormonal contraceptives or non-steroidal anti-inflammatories. While these options are inexpensive, Raina actually noted that relugolix will still be able to compete on some patients.

Raina Priyadarshini: Every woman who has had fibroids has used hormonal contraceptives at some point, but we also do have to understand that these agents are marked by the suboptimal efficacies. For example hormone contraceptives, they do help in managing the heavy menstrual bleeding that women go through, but they have really no effect in reducing the fibroid size, which is the underlying cause. So it’s basically like you get fibroids, you the doctor puts you on hormonal contraceptives, you take it for a while, you manage your symptoms, you stop taking it, it comes back, you have to take it again–provided your fibroid size has not increased. And if they have increased then you resort to the further classes of treatment. So they don’t really treat the underlying condition.

Second, about anti-inflammatory, they don’t even help with the menstrual bleeding part of the disease. What they’re good for is managing the pain that comes with it, the pelvic pain and the pain caused by excessive bleeding. So they do help, but even the efficacy is limited because they are also unable to act on the size of the fibroids. I believe that is the main reason that almost 60% of women, they failed the first-line therapies which leads them to use stronger drugs, such as GnRH agonists and the GnRH antagonists.

So when we compare these two broad subclasses of GnRH antagonists with agonists such as Lupron, the GnRH antagonists where relugolix belong, they definitely have the advantage of having a better safety profile. Lupron is contraindicated for people who have had cardiovascular problems, but the GnRH antagonist like elagolix and relugolix have a better cardiovascular safety profile.

Also when you administer the GnRH agonists, the action is delayed. There’s a receptor desensitization because of an initial flare-up effect. So that leads to a delay in the decreased amounts of estrogen in the body. So that takes around three to four weeks to take place, but relugolix and elagolix, which are GnRH antagonists, have a very rapid onset of action which really makes them one step superior to the GnRH agonists. The second thing is the ease of administration. These are oral pills which the patient can take and they don’t need to take a shot every time.

Mike Ward: Joan, what do you think are the major challenges relugolix actually might face in this indication of endometriosis-related pain?

Joan Tur: Without a doubt, combined oral contraceptives and non-steroidal anti-inflammatories which are used as first-line therapies and are considerably less expensive than the GnRH agonists or antagonists, as matter of fact. And that is despite their suboptimal efficacy, and the fact that they only manage symptoms, but not the cause of the disease.

Also the low treatment rates for both endometriosis and uterine fibroids is another contributing threat for the success of the drug. Because most of these patients go undiagnosed in most cases. So this is a great threat for relugolix’s success.

The drug will also face competition from GnRH agonists, particularly Lupron, which is a generic in the U.S. And also direct competition from other GnRH antagonists, Orilissa, which has the first market advantage for the class in both endometriosis and uterine fibroids.

Mike Ward: Those are the four non-COVID 19 drug compounds that are featured in this year’s Drugs to Watch. A report that is available for download.

So I’d like to thank Joan for his contribution today, and also to you for tuning into this episode, if you want to be notified about future episodes of Conversations in Healthcare, be sure to follow our LinkedIn page where we’ll be announcing new releases. Thank you.

Joan Tur: Thank you.