Thomas Wakim On Neuclone’s Early Dive Into Developing PD-1 Inhibitor Biosimilars

The Center for Biosimilars® (CfB):I'm Tony Hagen, senior editor for CfB. Today, we're talking with Thomas Wakim, strategic analyst for Neuclone, a biosimilar developer based in Sydney, Australia. Recently, Neuclone announced that it was adding to PD-1 inhibitors to its biosimilar development pipeline. Neuclone aims to develop PD-1 inhibitors for the blockbuster products pembrolizumab, otherwise known as Keytruda, and nivolumab, also known as Opdivo. Both drugs have been on the market for half a decade. They are indicated for numerous settings in oncology and their patient outcomes have been spectacular. They also enjoy phenomenal annual sales, which makes them a good target for biosimilar producers. Their patent exclusivity could start to end in 2027.

We sat down with Wakim to discuss Neuclone's interest in replicating these products. Neuclone is among the first companies to publicly announce interest in developing biosimilars of pembrolizumab and nivolumab.

What interests Neuclone in producing biosimilar versions of nivolumab and pembrolizumab?

Wakim: I guess to start off with from a clinical and patient perspective, since these 2 products were introduced about 5 years ago, they've dramatically improved the prognosis for many different cancer patients across a range of different indications. We see the great benefit that these medicines have had for so many different patients. And so, we want to be able to develop more affordable versions of these biosimilars so that it's not only those people who live in geographic locations where they can affordably gain access or patients who have the financial position to pay for the originator molecules [that have access to them].But we also want to bring more affordable versions, so that patients all around the globe who are suffering from a variety of oncology indications can receive these treatments.

And I guess if we look at the commercial side as well, these 2 products are some of the biggest products in the world at the moment. They’re only forecasted to continue growing into the future. I think, at the moment, their sales are around about $20 billion per year. And so, we see, from a biosimilar standpoint, that there's a great opportunity to introduce cheaper versions of these drugs to really bring down that health care expenditure and allow many more patients around the world to gain access to what are incredibly effective and beneficial oncology treatments.

CfB: What is the current annual cost for a treatment with either of these 2 drugs? Do you have a sense of what patients are putting out for these?

Wakim: Yes, well, so it varies country by country. Unfortunately, the United States is typically where patients have the most expensive treatments. So, the prices for these drugs are most expensive. It's difficult to know exactly what the cost is and who's paying for what. But, certainly, with a lot of these oncology products, we see upwards of over $100,000 per year, in many cases, to have a full annual course of these treatments. And so, it is very expensive, and many patients obviously can't afford that level of spending if they don't have comprehensive insurance or otherwise can source these products.

CfB: The patent expirations for these products are very important. You must have taken a close look at when you think you can bring these products to market and coordinated that with your development process. Can you explain what your timing is and what markets would be most appropriate for you?

Wakim: Yeah. So, as you mentioned, patent expiry is incredibly important for biosimilar developers. It reflects when we can enter the market. And so, with these 2 products, they are quite distant, expiring products. They themselves have only been available, I think for about 5 years now. And so, there is still quite a significant window until that exclusivity period does run out. And while biosimilars do have a more abbreviated development timeline compared to an originator molecule, it is still quite a time-consuming process to do the preclinical and the clinical stages that are still required.

And so, while there is still a significant window, we envision that probably towards the late 2020s. At least that's what the originator companies have reported publicly, that the patents on these products will begin to expire. And so, that gives us quite ample time to conclude our preclinical activities of these biosimilars and, in the coming years, enter into phase 1, and possibly phase 3, clinical trials so that, ahead of that exclusivity period ending, we can have our biosimilars’ development completed, approved, and ready to enter the market so that from day 1, we can really start to bring in affordable versions of these products, rather than having that lack of competition. And originator manufacturers continually increase their prices when that competition doesn't exist.

CfB: Have you picked any particular markets to enter? I know you work closely with the Serum Institute of India. So, is there a country or number of countries that you find most attractive early on to begin with?

Wakim: So, I think first and foremost, for all of our products, really, the United States and European regulatory standards are what we try and adhere to. We definitely view those as great opportunities where there's been a lot of biosimilar experience to date. The patients and providers are very familiar with biosimilars in those regions. And so, we look to follow EMA [European Medicines Agency] and FDA guidelines. By doing so, we are able to leverage approval in those regions and for several other jurisdictions. For example, Neuclone's local home market here in Australia has adopted EMA guidelines. And so, we envision that with an approval in Europe from the EMA, it would allow us to bring our products into the Australian market through the TGA [Therapeutic Goods Administration] relatively smoothly, as many other biosimilars have done in the past. And certainly, not just Europe, the United States, and Australia, but many other countries, such as India, as you mentioned, which is the home market of our manufacturing partner, the Serum Institute. We really are emphasizing trying to bring these products to as big of a global patient audience as we can.

CfB: What type of competition is out there? Is there anybody else racing to bring these biosimilars to market? Or do you think, at this point, you have the field to yourselves?

Wakim: I definitely don't think we have the field to ourselves. I think as we've seen today, biosimilars can be a very competitive space, particularly with a lot of these products, as I mentioned, that are quite mega blockbusters, where the sales are in many billions of dollars. They represent really favorable commercial opportunities for biosimilar developers. And so, we're envisioning, with Keytruda and Opdivo, having the huge markets that they have, that there will be many biosimilar players looking to develop their own versions of these products.

I think you only need to look at a couple of examples today of where similar situations exist for products like Humira [adalimumab], which is the world's biggest selling drug. There are at least 5 or 6 biosimilars available in Europe, and a similar number that are looking to enter the United States.

So, we do envision a high level of competitiveness. But we do feel that through our partnership with Serum and the work we do here at Neuclone, that we're pretty well positioned to compete in these price competitive and intensive markets when they do form.

CfB: Are there any special challenges with bringing a PD-1 inhibitor into development, besides the routine for biosimilars? You are already well-versed in working on biosimilars. So, what do you anticipate?

Wakim: I guess it's difficult to comment on the future clinical challenges that lay ahead. But what we can really focus on here at NeuClone is what we've focused on for at least the last 5 years now and that is the initial and early preclinical stages of development and doing the comprehensive science and technical development to get these products ready to enter the clinic.

As opposed to originator molecules, where we see the greatest risk is in the clinical side of development, for biosimilars, as is often described, the greatest technical challenges are in the early preclinical activities. And so, that's what we've been focusing on here at Neuclone. Our Neumax platform has allowed us to develop a whole range of upwards of 20 biosimilars, including our Opdivo and Keytruda candidates. And with those 2 specific ones, we haven't encountered any exceptional or any difficult issues. Obviously, every molecule is quite different. But with these 2, we're really happy with how they're progressing. We've got great, high quality products that are producing very well. And so, we really are looking forward to bringing these products into the clinic in the next couple of years.

The next step is figuring out exactly what that clinical program would look like. But what we've seen recently, in a couple of great papers, is that from all the biosimilars developed to date, the success rate in phase 1 and phase 3 clinical trials is incredibly high. And so, the emphasis on the early stage, in the preclinical activities, is very important. Getting that done early really reduces the risk that any differences would arise later in the clinical stages. We're feeling quite confident about these molecules and feeling pretty positive about the outlook moving forward.

CfB: What's the role of the Serum Institute as your partner in this venture?

Wakim: The Serum Institute is our manufacturing, co-development partner. Typically, what happens in our co-developed products is that Neuclone develops the products initially. We confirm the biosimilarity of the product and bring it to a certain stage and scale in-house, in our lab facilities here in Sydney. And then the Serum Institute takes that product and scales it up to manufacture a supply for clinical trials and, ultimately, a commercial supply of the product.

We have a partnership with Serum for 10 products. And so, Keytruda and Opdivo are 2 of those and all of our other disclosed products, to date, are also with the Serum Institute. We've had a really successful partnership over these first few years. We've been able to develop some really great biosimilars and get them into the clinic and prove that they meet all the biosimilar standards in terms of PK [pharmacokinetic] safety, as you would expect in these clinical trials.

And so, we're really looking forward to taking our partnership to the next step with the Serum Institute as we eventually get approval for these products so we can really see that large scale manufacturing that Serum is so well known for, traditionally in the vaccine business, now being applied to that biosimilar business through Neuclone products, where we have incredibly large scale production of our biosimilar products.

CfB: You mentioned 10 disclosed products. Can you tell us what those are, and which are closest to coming to the market?

Wakim: Yes, certainly. So, we've got 10 [biosimilars in development] with Serum, and 8 of those have been disclosed publicly. Just to quickly name them, they're Herceptin [trastuzumab], Stelara [ustekinumab], Prolia [denosumab], Perjeta [pertuzumab], Synagis [palivizumab], Humira, Keytruda, and Opdivo. They're the 8 and then, the other 2 with Serum and the other 10 that we're working on independently are all undisclosed at this point. But some of the nearer term products in that partnership would be our Herceptin and our Stelara biosimilar candidates. Those are the 2 clinical stage products that we have today.

So, in our overall strategy, we see products such as Stelara coming to the market first, and then, that will be followed by several other products, including our PD-1 inhibitor Keytruda and Opdivo biosimilars further on in the long term. And so, we envision having these multiple products coming through development and onto the market successively over a long period of time.

CfB: You came out with an announcement that you intend to go after these 2 drugs. Was there any strategy behind making that announcement or was there something more to it?

Wakim: I mean, there's nothing incredibly detailed to it. We have a range of products in our pipeline. And so, we felt that with Keytruda and Opdivo, we had developed a sufficiently to a point where we were comfortable in really announcing to the world that we have these biosimilars, they're looking great, and we're really confident in them. And so, it was more from the perspective of really just being fully confident that the Keytruda and Opdivo originators are looking really good and we're really confident in them and being able to bring them through the clinic in the coming years. So, it's more from that perspective.