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Using lessons learned from the first wave of biosimilar approvals – and citing high prices in the US – some developers are starting to 'think small' with biosimilars for rare disease markets. Alexion’s Soliris is a case in point.


The initial market for biosimilars has centered on large-market opportunities like Genentech’s Rituxan and AbbVie’s Humira. But behind that first wave are unique opportunities in much smaller markets – with some companies already eyeing pure-play orphan biosimilars to treat rare diseases.



Given the biosimilars market is still in a prolonged early phase (especially in the US), it may seem premature to begin thinking about ways to develop orphan biosimilars. But the evolving regulatory and scientific landscape is creating a knowledge base for application to small-market biosimilar opportunities. (Also see "The Birth Of An Orphan Biosimilar Market" - Pink Sheet, 17 Feb, 2016.)



In one sense, orphan biosimilars are already available in the US, given that the five broad-market biosimilars approved by FDA have orphan indications in the label. For example, Johnson & Johnson’s TNF inhibitor Remicade (infliximab) has served as the reference drug for two FDA-approved biosimilars and carries with it an indication for the treatment of pediatric Crohn’s disease, an orphan disease. But the approval of a pure-play orphan biosimilar is still a while off, as most developers are getting their feet wet in large markets before making a higher-risk investment in rare diseases.



That said, one opportunity already receiving some attention from biosimilar developers is Alexion Pharmaceuticals Inc.’s Soliris (eculizumab). Soliris is approved for two ultra-rare blood disorders: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. At least two biosimilar eculizumab products are in development: Amgen Inc.’s ABP 959; and BOW080, which was recently divested by Epirus Biopharmaceuticals Inc. to an undisclosed buyer.



Carrying an annual price tag of about $600,000 per patient, the commercial opportunities alone make Soliris an attractive target, but its specific clinical profile and market position may make it particularly enticing for biosimilar development.



Epirus’ former President and COO Michael Wyand recalled his experience with BOW080 during a panel discussion at the World Orphan Drug Congress in late April. Epirus acquired BOW080 (among other biosimilar candidates) in 2015 from privately held, Netherlands-based Bioceros Holding, and estimated filing an application in 2020. Epirus subsequently filed for Chapter 7 bankruptcy protection in July 2016 and sold most of its holdings.



But Wyand believed then – and still believes – that eculizumab is an attractive target for biosimilar development, for the following reasons: 1) a wide target for attractive pricing underneath the innovator brand; 2) a relative lack of competitors under development; 3) a clear surrogate marker that could eliminate the need for a clinical trial to demonstrate biosimilarity; and 4) a hematology community that may be receptive to using an eculizumab biosimilar.



On that last point, Wyand underscored the importance of buy-in from the health care community, especially in the US, where many physicians are still skeptical of biosimilar products. In Europe, he said, “everyone is on board with biosimilars,” given the decade of experience and a generally more socialized approach to health care. Epirus’ discussions with US clinicians on biosimilars, however, were drastically different. He heard: “What are these things? Why would I ever want to use one when I can have the innovator product? They wanted a lot of data.”



Within the hematologist community that uses eculizumab, however, the conversations were much more positive. In meetings with 30-35 hematologists in the US, the vast majority told Epirus they would be willing to enroll their next new patient in a clinical trial for an eculizumab biosimilar. The reason, Wyand said, was the price of Alexion’s innovator biologic. Hematologists said: “This [price] is too high. We need to do something about getting drug prices down. So I came to the conclusion that we could enroll that trial quite easily in the US.”



Challenges To Orphan Biosimilar R&D


Soliris is likely an outlier in its near-term feasibility for biosimilars. Generally speaking, orphan biosimilar developers face a triple whammy of the evolving 351(k) approval pathway; difficulty in manufacturing large molecules; and the inherent obstacles to developing treatments for small markets.



During the World Orphan Drug Congress, PRA Health Senior Director of Biosimilars Development, Scientific Affairs Hazel Gorham rattled off a list of R&D challenges specific to orphan biosimilars: a relative lack of historical data; small patient numbers for clinical trials; hurdles in accessing (and paying for) samples of the comparator biologic; and successfully engaging with various regulatory agencies on designing a quality package for submission.



From a commercial perspective, small patient populations mean that being first to market is even more important for orphan biosimilars. Wyand, the former Epirus executive, said that developers have to question the economic value of being the second or third biosimilar to the market. “In the orphan drug space, it’s difficult with small number of patients,” he said. “I don’t see how it can happen.”



“If you are going to make an investment five or six years before patent expiry and race to the market, that’s going to be a little bit higher risk than the bigger markets from a business perspective,” Wyand said. In the case of eculizumab, Epirus determined that the commercial risk would pay off: “There was not a lot of activity at the time that we started our program that we could see for biosimilar Soliris.”


FDAs Pledges “Flexibility”


What would help to encourage development of all biosimilars – but particularly in rare diseases – is for FDA and industry to find a way to demonstrate biosimilarity without needing to run a clinical trial. In the case of eculizumab, Epirus “really did fully believe that a surrogate marker, something less than a fully powered Phase 2 trial, could be very convincing of clinical equivalence.” While FDA’s guidance documents on biosimilar development are written to anticipate a scenario where clinical trials are not necessary, “we don’t have a good way to show right now that it’s not necessary,” Wyand said. “It’s still hard to see how we can get there.”



Leah Christl, associate director for therapeutic biologics in FDA’s Office of New Drugs, agreed that the agency tried to build in a “fair bit of flexibility” to demonstrate biosimilarity. The scientific final guidance document on biosimilars, for example, suggests that a clinical comparative study may not be required if biosimilarity can be demonstrated in animal data or human cells.



Christl pointed to the development of the first approved 351(k) biosimilar, Zarxio (filgrastim-sndz), in which Sandoz demonstrated biosimilarity through a Phase IIB comparison, not efficacy endpoints. But, she added: “the dearth of some scientific information is where the challenge is. A lot of times, products work, but we don’t know why they work.” For orphan drugs specifically, Christl said, more information collected during the initial development program will benefit biosimilars later.



But there isn’t much FDA can do to shorten the development timeline specifically for biosimiliars for rare diseases. Unlike innovator drugs and biologics, which can qualify for any number of accelerated development and regulatory pathways (like Breakthrough Therapies, Fast Track, Accelerated Approval and priority review), for biosimilars, there is just one pathway. “The biosimilar pathway is the biosimilar pathway,” Christl said. As such, the standards to demonstrate biosimilarity are the same – regardless of the size of the market.



Boehringer Ingelheim GMBH Associate Director of Public Policy, Biosimilars, Pipeline and Reimbursement Molly Burich said her company is still trying to figure out the 351(k) pathway for large-market products before it can consider investing in orphan opportunities. BI is in Phase 3 with two biosimilar candidates (adalimumab and bevacizumab), but was forced to abandon a third (rituximab).



“We have to get good at the big ones, and learn some tough lessons while we can still recoup our investment before we’ll get to a point where an orphan drug makes sense from a clinical and business investment standpoint,” she said. “I think it will come,” but “we have to have enough experience and enough successfully marketed products to build the collective evidence in the US that we are starting to see build in Europe.”

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