Tag: FDA

A Test for Adello and for FDA’s Biosimilar Approval Pathway

We are on the verge of a few eagerly awaited decisions by the Food and Drug Administration (FDA). Celltrion and its partner Pfizer expect to hear news on their trastuzumab biosimilar in April, as does Celltrion separately on its rituximab biosimilar. These should make a significant impact on the evolution of biosimilars in the US and on marketshare penetration, but the FDA’s decision around the fourth filgrastim agent from a lesser- known player could be even more important to the industry.

One of the critical areas that differentiate 351(k) from 351(a) biologic licensing applications (BLAs) is that the FDA has emphasized the primary importance of evidence supporting the pharmacokinetic, pharmacodynamic, and structural similarity of the biosimilar to the originator product. In comparison, the standard BLA requires a sufficient catalog of data from phase 1, 2, and 3 clinical trials that point to the efficacy and safety of the biologic. To many in the biosimilar field, the inverted pyramid illustration left is very familiar.

351(k) biosimilar approval requirements

To date, the biosimilars brought to the application or registration process have been evaluated on their physiochemical characterization as well as the results of phase 2 and/or 3 clinical trials in at least one target indication. This is where it becomes interesting: Adello Biologic’s 351(k) application for filgrastim comprises the physiochemical biosimilarity evidence, but in terms of clinical data, only phase 1 studies were performed. That is, these studies included healthy volunteers only. And the studies further demonstrated the comparable pharmacokinetics and pharmacodynamics of this biosimilar and Neupogen®, the originator G-CSF drug.

This decision was not made in a vacuum. The manufacturer consulted with the FDA, as all prospective biosimilar makers do, on the requirements of their data packages. And the FDA accepted the application in September 2017. This fits with the agency’s policy to place ever-increasing weight on the physiochemical data as part of its “totality of evidence” approach. In its 2015 guidance, the FDA stated, “As a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human [pharmacokinetic and pharmacodynamic] data, and clinical immunogenicity assessment.” With Adello’s filgrastim, one assumes that the FDA made the decision that the studies in healthy volunteers was sufficient.

Since Adello would be the second filgrastim biosimilar approved (also the fourth filgrastim on the market), the FDA may decide to dispense with an Advisory Committee meeting to discuss publicly the merits and issues with the agent. However, because this could be the first biosimilar approved without phase 2 or 3 clinical data, the FDA may decide on a conservative course, allowing the clinical community and the public to weigh in.

One could see how the lack of clinical data in actual patients will give pause in an Advisory Committee session. A patient undergoing cancer chemotherapy will likely have a different immunologic status, it can be argued, which may result in immunogenicity problems in real-world use. For agents already marketed in Europe, such issues may be absent and can be considered as part of the totality of evidence. Adello, however, does not market their biosimilar elsewhere.

Even if the Advisory Committee does not recommend (or a slight majority recommends) approval, the FDA could decide to license the drug anyway, in view of its stated policy to get biosimilars to market more rapidly. If this is the case, it would help ensure that R&D costs remain as low as possible for prospective biosimilar manufacturers, without the requirement of performing expensive phase 2 or 3 trials.

The question of whether an Advisory Committee will be held is still unknown. In response to queries, an FDA spokesman offered that the agency had “previously articulated a general expectation that a proposed biosimilar to a given reference product would be discussed at an Advisory Committee meeting if a proposed biosimilar to that reference product had not previously been discussed at an AC meeting. Subsequent proposed biosimilars to a given reference product may also be discussed at an AC meeting if FDA determines that there are specific issues to discuss.” In other words, no one knows. A query to Adello was not answered as of the publication of this article. Any updates will be noted in this space.

 

A Profile on Lesser-Known Player in the Biosimilar Space: Lupin Pharmaceuticals

On occasion, we profile some biosimilar manufacturers about whom our readers may not be as familiar as the large players like Sandoz, Amgen, and Pfizer. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight a Baltimore-based company, Lupin Pharmaceuticals.

Lupin is a subsidiary of the Indian company Lupin Limited. It is perhaps best known as a manufacturer of generic drugs, especially anti-infectives.

Why you may be hearing more about this company: At a January JP Morgan investor conference, Lupin announced its intention to bring a biosimilar application for etanercept to the European Medicines Agency in early 2019, with a 351(k) application filed with the Food and Drug Administration the following year. Additionally, Lupin has indicated that it will be jumping into the biosimilar market with both feet, with early-stage development beginning for six other medications: aflibercept, denosumab, filgrastim, pertuzumab, pegfilgrastim, and ranibizumab. It believes that the combined global market for these agents is $24 billion.

Lupin has not announced any marketing partnerships, meaning that they may decide to go it alone, unlike some of the major players (e.g., Allergan–Amgen, Celltrion–Pfizer, Samsung Bioepis–Merck, etc). With its extensive generic portfolio, Lupin may believe that it has the sales force necessary to effectively market in the biosimilar space as well.

In other news…Novartis has announced an unusual clinical trial move. In its clinical trial program for secukinumab (Costentyx®), it has engaged in a head-to-head trial against both Humira® and its own (i.e., Sandoz’s) biosimilar version of adalimumab (GP2017).  The head-to-head trial with GP2017 focuses on the ankylosing spondylitis indication, whereas the Humira comparative-effectiveness trial involves patients with psoriatic arthritis.

Fourth Herceptin® Biosimilar Being Evaluated by FDA

The end of 2017 has been bustling with oncology biosimilar news.

On December 20, 2017, the Food and Drug Administration (FDA) accepted Samsung Bioepis’ application for SB3, its biosimilar version of trastuzumab. The drug would be the fourth to undergo evaluation by the FDA, and may pack on the pressure for Mylan and Biocon’s product Ogivri™, which is the only approved biosimilar trastuzumab.

Mylan/Biocon’s biosimilar was approved earlier this month. As a reminder, though, there are no plans to bring their version of trastuzumab to market immediately. Indications are that Breast Cancerowing to an agreement with Roche, they may not launch until 2019 (at the earliest). Trastuzumab biosimilar entries by Celltrion and Amgen/Allergan will not receive FDA decisions until the second quarter of next year. It is unclear whether these manufacturers will decide to launch their versions at risk, thus stealing the initiative from Mylan and its partner. In any case, competition should be vigorous when these products launch (which should be within 12 months of the first launch, assuming FDA approvals). At present, the question is open as to whether Samsung will market SB3 if it receives a positive decision sometime in the fourth quarter of 2018.

In related news…A survey of 200 oncologists revealed that their comfort levels with prescribing biosimilars is widespread. Cardinal Health published a report based on the survey on December 20.

Although these result may relate to oncologists’ multiyear experience with Zarxio® (filgrastim), 82% of the oncologists responding to the survey specifically indicated that they would have no qualms about using biosimilars to treat patients with breast cancer in an adjuvant setting or if they had metastatic disease. As indicated above, no biosimilars are currently marketed for this indication. Furthermore, they expect significant cost savings when using biosimilars: Two thirds said that cost savings with biosimilars are either extremely or very important in their prescribing decision. That’s pretty much the point of biosimilars, isn’t it?

Accounting for Lot-to-Lot Variability of Biologics in Biosimilar Development

In creating the 351(k) US biosimilar approval pathway, regulators had laid out a methodology in which the totality of evidence is weighted heavily by proof of structural and pharmacologic comparisons of the biosimilar to the originator product (unlike the most critical role of clinical trials in the conventional 351(a) regulatory pathway). Through the initial approvals by the Food and Drug Administration (FDA), the level of scrutiny given to these physical, pharmacodynamics, and pharmacokinetic evaluations has become clearer.

In its latest draft Lee 2guidance, the FDA has added some more direction, as well as emphasizing one of the key points of the biosimilar and biologic manufacturing process. They spotlight the level of variability of one biologic. Recognizing the potential for variation in one reference biologic, the 351(k) approval criteria include comparisons versus copies of the US-licensed (rather than EU-licensed) originator product. For some approvals, bridging studies, which also test the similarity of the EU- and US-licensed biologics, have been permitted. In the guidance, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” released earlier in September, the FDA further amplifies this requirement.

In the biosimilar development process, a prospective manufacturer must obtain samples of the biologic from the originator drug maker. However, as has been well documented, lot-to-lot differences in the biologic may well occur, though these are not expected to have implications for clinical safety or effectiveness. Proving structural similarity to this agent goes a long way to progressing down the path to approval. In its draft guidance, the FDA seems to expand its test for analytical similarity. The biosimilar manufacturer must obtain “a minimum of 10 reference product lots” and these lots “should represent the variability of the reference product,” against which the biosimilar drug is evaluated to allow for meaningful comparisons. In other words, the biosimilar manufacturer must consider the likelihood of variation in the local source of the biologic. The FDA is accepting public comments on its draft guidance for 60 days.

This has some basic implications for biosimilar manufacturers. To begin the process of engineering a biosimilar drug, they must obtain samples of the originator product from its manufacturer. This has not always been simple, as the drug maker defending its brand can delay the process or otherwise make it difficult to purchase. Some legislative proposals have been introduced to coerce the originator manufacturer to provide, in a timely manner, the samples required by the prospective biosimilar drug company (e.g. Fair Access for Safe and Timely Generics Act of 2017).

The Week in Biosimilar News

You know it’s been a pretty desperate week in the biosimilar blogosphere when twitter feeds relate back to articles published in January, rehashes of the US Supreme Court decision in June, or yet another estimate of the savings potentially ascribed to biosimilar use (based on erroneous assumptions). However, there were a few significant tidbits announced last week that are worth reviewing.

First, Biocon announced that the decision to approve its trastuzumab biosimilar (with partner Mylan) has been delayed by the Food and Drug Administration (FDA) 3 months (until December 3, 2017). According to Biocon, this delay was required so that the FDA could “review some of the clarificatory information submitted as part of the application review process.” Clarificatory? Really? Maybe the extra time was needed to translate the application itself.

Second, a survey of 103 US gastroenterologists raised a couple of questions as to how well information about Inflectra®, the biosimilar to Remicade®, is sinking in on the practice level. According to a press release from Spherix Global Insights, cross-category prescribing may be interfering with the uptake of the biosimilar. They state, “not only is the decline [in Remicade prescriptions] attributed to the adoption of infliximab biosimilars, but use of Humira® has also significantly increased, potentially indicating that more ulcerative colitis patients are being placed on Humira to avoid insurance mandates for infliximab biosimilar use.” This limited survey found that more than one-third of gastroenterologists “agree that if a pharmacy or managed care plan advises them to use Inflectra over Remicade, that they are more likely to choose a different TNF-inhibitor altogether.” This is a weird finding, perhaps indicating nothing more than spite for the health plan’s benefit design. Clearly, if the physicians fully considered the evidence, they would be less likely to prescribe in this way. Admittedly, as notable numbers of managed care organizations have not actually mandated Inflectra use at this point in time, we would have to wait to see if this opinion is validated in actual practice.

Finally, Sanofi announced that it had received tentative approval on a follow-on biologic form of insulin lispro (the originator product was Lilly’s Humalog®). Patent issues will have to be resolved before Sanofi can receive final approval and bring this product to the market. The insulin biosimilars are not regulated under the Biologics Price Competition and Innovation Act, but rather under the Hatch–Waxman Act—the application was filed as a 505(b)2 rather than a 351(k) variety. They are transitional products, which will considered under the newer regulations after March 23, 2020. We will detail these lesser-known transitional drug categories in a future post.

FDA Approves New Humira Biosimilar, Bypasses Advisory Board Route

Boehringer Ingelheim Pharmaceuticals, Inc. announced August 29 that it had received approval from the Food and Drug Administration (FDA) for its first biosimilar. Named Cyltezo™ (adalimumab-adbm), a biosimilar to Humira®, it is approved for several autoimmune disorders, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease in adults, plaque psoriasis, and ulcerative colitis.

The FDA approval bypassed the need for an Arthritis Advisory Committee review and recommendation, which the agency suggested may be increasingly common with future biosimilar approvals. One suspects that this is more likely with the licensing of the first biosimilar for a particular originator product, with the assumption of a comprehensive data package on submission.

Like Amgen’s Amjevita®, Boehringer’s biosimilar will likely enter a holding pattern until patent litigation is settled (or the patents expire) on AbbVie’s Humira. In the meantime, Boehringer indicated that it will seek approval for an autoinjector, to stand alongside its newly approved subcutaneous formulation.

Boehringer has also applied for approval with the European Medicines Agency, which is expected to decide on its approval before the end of this year. Samsung Bioepsis and partner Biogen earned its own European approval for Imraldi™ this week, another adalimumab biosimilar.

Mylan and Biocon Withdraw Two EMA Biosimilar Applications

The biosimilar pegfilgrastim marketplace may have taken another hit today, as Biocon announced that it was pulling its applications for both pegfilgrastim and trastuzumab from consideration by the European Medicines Agency (EMA).

The action came after Biocon was notified of the need for re-inspection of its manufacturing site by the European authorities. According to Reuters, Biocon said in a stock filing, “The European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products,” Biocon said, without specifying when the regulator would carry out the inspection.

Herceptin“We are on track to complete our corrective action and preventive actions by the end of this quarter, and it is our intent to seek re-inspection and re-submission thereafter.”

In another report, a Biocon spokesperson stated that “Whilst our drug substance facilities for trastuzumab and pegfilgrastim were approved, the European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products. The request for withdrawal of the dossiers and re-submission is part of the EMA procedural requirements linked to this re-inspection and will be considered by the EMA’s Committee for Medicinal Products for Human Use (CHMP),” said the company spokesperson.

This action could potentially create considerable problems for the partners Mylan and Biocon. They have the opportunity to be first-to-market in the US with regard to both biosimilar products. Their biosimilar trastuzumab application received a unanimous recommendation to approve from the Food and Drug Administration (FDA) Oncology Drug Advisory Committtee in July, and a final decision is imminent (expected before September 3). The partners’ biosimilar pegfilgrastim application is expected by October 9th. Although the FDA usually rules according to its Advisory Committee recommendations, manufacturing plant problems has resulted in at least one surprising rejection, for Pfizer’s Retacrit®. Pegfilgrastim applications have not yet made it through the FDA approval process, after three previous attempts.   

Information is not readily available as to whether the Biocon plant that is subject to re-inspection would potentially be supplying products to the US. If so, the FDA may decide to review the situation, and possibly delay their decision or issue complete response letters on the two products.

Two New Trastuzumab Biosimilars Submitted for FDA Approval

The team of Mylan and Biocon may have some company in the biosimilar competition for Herceptin® (trastuzumab). Two additional partnerships announced the filing of their 351(k) applications for trastuzumab biosimilars.

Amgen and Allergan are hoping ABP 980 will have smooth sailing through the approval system. The phase 3 study in patients with early-stage HER2-positive breast cancer was completed in January 2017, with study results reported in July 2016. This study enrolled 725 patients, and yielded positive results in terms of safety, efficacy, and similarity to the originator product.

Celltrion submitted their product application for CT-P6 (Herzuma™) to the FDA on July 30 as well. Its partner Teva will distribute and market the product in the US, upon approval. The phase 3 study for this product is ongoing, but the results of the primary outcome data from 549 patients were published in June 2017. The outcomes were found to be similar to those of Herceptin.

Mylan and Biocon had submitted their biosimilar version on November 1, 2016. The FDA Advisory Committee reviewing their product gave it their unanimous support on July 13, and the final FDA decision is expected by September 3, 2017. If approved, Mylan will have at least a 9-month time advantage to get their foot in the door of a $2.6 billion trastuzumab marketplace.

This sets up a very interesting pricing dynamic. I had originally thought that this scenario might occur first with adalimumab after the patent litigation was resolved, but it is very possible that multiple biosimilars for trastuzumab may be launched first and in a very short timeframe.

Assuming Mylan gets the nod from FDA first, they have a couple of obvious paths they can travel: (1) launch with a substantial discount in an attempt to capture as much marketshare as possible before the other market entrants arrive or (2) launch with a modest (but attractive) discount in an effort to maximize their revenue while their product remains the sole biosimilar available. It will then be a guessing game as to how Amgen/Allergan and Celltrion/Teva play their turns in this poker game. With sudden market competition, such as their launches could potentially pose, payers may play a bit of a waiting game themselves, to see where the chips fall.

Boehringer May Seek Interchangeable Designation for Adalimumab Biosimilar

The US Food and Drug Administration (FDA) announced earlier this year its draft standards for assessing the interchangeability of biosimilars with originator products. One biosimilar developer announced on July 27 that it is embarking on a study specifically to prove interchangeability of its biosimilar version of adalimumab.

Initial recruitment of the “VOLTAIRE-X Pharmacokinetics, Safety, Immunogenicity and Efficacy of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis: A Randomized, Double-Blind, Parallel-Arm, Multiple-Dose, Active Comparator Trial” was announced by Boehringer Ingelheim to provide evidence that its investigational biosimilar BI 695501 can be substituted for Humira without significant negative clinical or safety effects. The study will incorporate repeated switching between the originator and the biosimilar agent in 240 patients with plaque psoriasis.

Boehringer’s 351(k) application for BI 695501 was sent to FDA in January 2017. A decision is expected in the fourth quarter. The clinical studies supporting BI 695501 were conducted in patients with rheumatoid arthritis; another is underway in patients with active Crohn’s disease. The VOLTAIRE-X interchange study will not be completed until July 2019; therefore, any FDA decision regarding interchangeability on this biosimilar will be made at least 2 years from now.

Will Approval of an Interchangeable Biosimilar Mean that Others Are Inferior?

In terms of the biosimilar market and utilization, the US has been at least one full decade behind Europe in every respect but one. Yes, we have the EU beat in a game they avoided playing: The interchangeability gambit. The Europeans never defined interchangeability as a separate concept for biosimilars, thus leaving the individual countries to decide whether to allow unencumbered switching of biosimilars for their originator drugs.

As in other areas of biosimilar policy and regulation, the US started very slowly. Leah Christl, PhD, Associate Director for Therapeutic Biologics, OND Therapeutic Biologics and Biosimilars Team, Food and Drug Administration (FDA) stated last week at the Drug Industry Association’s annual meeting in Chicago that she expects the first interchangeable biosimilar to be approved within about 2 years. This is probably realistic, based on the timeline of the adoption of the agency’s interchangeability guidelines. Comments on the draft guidance are being read by the FDA at this time. Seven years after the passage of the legislation calling for the biosimilar approval pathway. If there were competitors in this game, we’d be desperately trying to catch up!

It seems unlikely that the FDA has any active 351(k) applications seeking the interchangeability designation, although Dr. Christl did not reveal whether this was the case. The application process is confidential; a submitted application is publicized only if the drug maker issues a press release on its ownDeck 1.png. It would seem premature to seek the interchangeability designation before the FDA’s own guidance on what the review entails is released. This may not prevent a biosimilar manufacturer that has already received approval from taking the quick step towards interchangeability, especially if they have conducted a series of switching studies that meet the FDA’s criteria (e.g., NOR-SWITCH).

Payers are chomping at the bit for an interchangeable product in the 36 states (and 3 pending) that have signed legislation allowing pharmacies to automatically substitute a biosimilar for an originator biologic.

Others have pointed out that the interchangeable biosimilar may be a boon to its manufacturer, but it may have negative effect on competitive markets. For example, a noninterchangeable infliximab may be considered by prescribers or patients somehow inferior to the interchangeable version, devaluing this biosimilar. On the other hand, the maker of “infliximab-int” could experience increased demand and boost prices (or avoid decreasing prices in the face of other noninterchangeable biosimilars coming to the market). And this may be justified. No one really knows the manufacturer’s incremental cost of achieving this designation, based on:

  • The cost of conducting additional switching studies
  • The potential cost of responding to FDA requirements for more data
  • The opportunity cost in marketing time, resulting from a delay in the application or approval

The race for a product with this extremely valuable designation drags on at a snail’s pace. I hope I’m still writing about it by the time someone reaches the finish line.