Coherus Gets FDA Approval for Its Pegfilgrastim Biosimilar

With the Food and Drug Administration (FDA) approval today of Coherus Bioscience’s Udenyca™ (pegfilgrastim-cbqv), the second pegfilgrastim to compete with Amgen’s Neulasta®, much attention will be now focused on the company’s November 8 earning call.

The FDA approved Udenyca on the basis of a supportive analytical similarity package, but with phase 1 data only. Over 600 healthy subjects were given the agent to test its pharmacokinetic, pharmacodynamic, and immunogenicity safety.

We should learn a great deal by the end of the week about the nature of the competition for the injectable pegfilgrastim marketplace into 2019. In the press release announcing the approval, the company said it will reveal its launch plans, including pricing, during its week’s call. On Monday, November 5, we should hear the first information about whether Mylan’s first-to-market entry, Fulphila®, has gained some traction against the injectable form of Neulasta. Mylan launched Fulphila at the end of July.

In a previous post, we discussed how Amgen’s Neulasta Onpro® patch has already captured upwards of 80% of the pegfilgrastim business. Because of the convenience of the patch formulation, it would be surprising if Onpro’s share of market eroded significantly. However, Amgen must ensure that the net cost difference between the biosimilars and Neulasta Onpro is not noteworthy. Otherwise, payers’ can be expected to try to disadvantage Onpro through step edits or greater patient cost sharing. That would take a sizable bite out of Amgen’s large slice of the $4 billion pegfilgrastim pie.

The FDA approved Udenyca for the following indication: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. It was not approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. This indication language does not differ from that for Fulphila. Neulasta has the additional indication of increasing survival in patients acutely exposed to myelosuppressive doses of radiation.

Undenyca was also approved for sale in the EU, although Coherus has not launched there, awaiting a marketing partner.

Pfizer Gets FDA’s Green Light on Its Filgrastim Biosimilar

Pfizer's Biosimilar Filgrastim
FILE PHOTO – The Pfizer logo is seen at their world headquarters in Manhattan, New York, U.S., August 1, 2016. REUTERS/Andrew Kelly/File Photo

On July 20, the US Food and Drug Administration (FDA) approved the second biosimilar version of filgrastim. Pfizer’s filgrastim biosimilar is named Nivestym™ (filgrastim-aafi).

The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio® [filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.

The FDA granted Nivestym the following indications:

  • To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
  • For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
  • To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
  • For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
  • For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

Although a launch date was not announced for Pfizer’s filgrastim biosimilar, the company’s press release stated that “Nivestym is expected to be available in the US at a significant discount to the current wholesale acquisition cost (WAC) of Neupogen.”

Rather than competing aggressively for the filgrastim market, Amgen seems to be focusing its efforts on its pegfilgrastim brand, a longer-lasting version. Specifically, it is seeking to move its utilization to the Onpro formulation of Neulasta®. The first biosimilar to pegfilgrastim was approved in June (Mylan and Biocon’s Fulphila™).

Mylan and Biocon Land First Pegfilgrastim Biosimilar Approval

The race to bring a pegfilgrastim biosimilar to market officially started on December 17, 2014. The checkered flag fluttered 3½ years later on June 4, 2018, with the Mylan/Biocon team winning on a slow track. The partners earned approval from the US Food and Drug Administration (FDA), becoming the first biosimilar to challenge for this $4 billion market.

Mylan will market the product in the US, and it is assumed that the product will be launched shortly,= to take advantage of their window of opportunity. The drug will be called Fulphila™, and the FDA assigned a formal name of pegfilgrastim-jmdb. The next likely competitor, Coherus, is expected to receive word from the FDA by November 2. Mylan will have the chance to quickly grab marketshare if they produce attractive deals for payers.

What Is the Biosimilar Pegfilgrastim Market Opportunity?

We’ve covered the contest to bring a biosimilar pegfilgrastim to market, with considerable depth. The progress and setbacks of Mylan/Biocon, Coherus Biosciences, Sandoz, and Apotex have been tracked. Other drug makers are also working on plans towards 351(k) applications for approval. Eventually—likely sooner than later—one or two will hit the market.

Biosimilar Pegfilgrastim, Neulasta®, and Onpro®

Amgen, maker of the originator product Neulasta®, disclosed in its first-quarter financial report that the total sales for the product in the US is $1.0 billion, $146 million for the rest of the world, for a total of $1.15 billion. This means a US market of approximately $4 billion for one year of sales. Amgen also noted that 62% of its first-quarter Neulasta sales are associated with its Onpro® kit. Although the major patents for pegfilgrastim have expired, Onpro is still protected by patent. Onpro does have some significant advantages in that the patient does not need to go to the doctor’s office for an injection after receiving chemotherapy. The sales figures indicate that doctors prescribe it in preference to the injectable form of pegfilgrastim.

Neulasta OnproAt a current 62% marketshare for Neulasta Onpro, the initial total slice of the pie available for biosimilars may only be $1.5 billion (not considering WAC discounts). If we assume a 20% discount, this may be closer to $1.2 billion. It may not seem logical for Amgen to make great efforts to defend its share of injectable pegfilgrastim because of its successful conversion to Onpro. Also, Onpro does have marketable advantages over the injectable form.

The list price of Neulasta is upwards of $7000 per injection, and Amgen does not charge additionally for the Onpro kit. This stance may prove an incentive to health plans and insurers to not encourage biosimilar use over Onpro.

Will Physicians Resist Moving From Onpro to a Biosimilar Pegfilgrastim Injection?

The $1.2 billion to $1.5 billion estimate also assumes that Amgen cannot convert more patients to Onpro prior to approval of a new biosimilar. That would further shrink the revenue opportunity. Physicians may also resist payer efforts and not prescribe the injectable form if they favor the Onpro kit. To the extent that payers may prefer the biosimilar (or otherwise restrict the use of a more expensive originator agent) when it becomes available, that slice of the pie could increase quite a bit. Furthermore, the picture could also change in a few years as biosimilar manufacturers develop delivery systems that gain the same advantages as Onpro.

In its earnings report, Amgen indicated the sales of Neulasta have been decreasing, by 5% from the same quarter last year. This may be the result of movement to other, less-toxic cancer chemotherapies or other treatments to prevent neutropenia and its related infections.

The Onpro market for the rest of the world may be given a boost soon, as Amgen also announced that the European Medicines Agency issued a positive opinion for the drug maker to include the Onpro Kit in its EU label.

As reported in BR&R, Coherus CEO Denny Lanfear thought the pegfilgrastim market may be split in a manner similar to that for filgrastim (i.e., 30%/30%/40% shares for 2 biosimilar makers and the originator). That may possibly mean 30% of a $1.2 billion US market (not $4 billion), if payers do not emphasize the use of the biosimilar over Onpro.

Coherus Biosciences Shows Major Stock Gain Upon BLA Resubmission

When it received a June 2017 complete response letter from the Food and Drug Administration (FDA), the outlook for Coherus Biosciences was cloudy. Its lead product, a biosimilar for pegfilgrastim (CHS-1701), had been cited for the way the drug maker evaluated immunogenicity and for manufacturing plant issues. Upon receiving the news, it cut 30% of its workforce.

Furthermore, Coherus has had little luck in challenging the existing patents of originator products. It was denied inter partes review on a key patent held by Abbvie on Humira® as well as a patent on Enbrel® by Amgen.

Today, Coherus may be on the verge of a turnaround in fortunes

Armed with new immunogenicity data, Coherus resubmitted its 351(k) application with the FDA on May 3, and investors reacted strongly to its new prospects. The company’s stock price soared 17.3% for the dCoherus Biosciencesay, closing at $14.90. Its previous 52-week low was $8.05. Coherus is a U.S. manufacturer that is focused solely on biosimilar development (a “pure-play” biosimilar maker).

In the company’s announcement, Coherus reported that the new FDA application is “supported by similarity data from analytical, pharmacokinetic, pharmacodynamics, and immunogenicity studies comparing CHS-1701 and Neulasta and integrates new immunogenicity data obtained from using a more revised immunogenicity assay.” Mr. Lanfear said, “The CHS-1701 BLA resubmission marks a significant milestone in our ongoing transition to a commercial company as we tightly focus on execution of our strategic plan.”

In April, Coherus filed for a rehearing of the etanercept inter partes review.

Coherus originally filed its pegfilgrastim biosimilar application with the European Medicines Agency November 29, 2016. According to a report from early in 2018, Chief Executive Officer Denny Lanfear asserted that he hoped to receive EMA approval in the second half of 2018.

News in the Courts on Biosimilars

According to a Reuters report, Janssen Biotech withdrew its patent lawsuit against Samsung Bioepis on November 10. The suit alleged infringement in the manufacture of Samsung’s infliximab biosimilar.

Related imageThe action, which was filed in U.S. District Court of New Jersey, means that Merck and Samsung, which launched Renflexis™ in July, is no longer at risk for revenues earned in the sale of its biosimilar. If Janssen had maintained the lawsuit and later earned a victory in the courts, it could have been awarded a large percentage of Samsung’s Renflexis revenues.

In a separate case, an appeals court found that the Southern District of Florida was correct in its decision clearing Apotex Inc of any patent infringement in its development of biosimilars of Amgen’s Neulasta® and Neupogen®. The initial ruling, in September 2016, helped cleared the path for the biosimilars to reach the market. However, the organization’s filgrastim biosimilar was first filed in February 2015, without an approval. Its pegfilgrastim biosimilar was filed earlier, in December 2014, but has not advanced through the Food and Drug Administration’s 351(k) approval process. Apobiologix is the Apotex subsidiary that would manufacturer and market the biosimilars in the US, should they gain approval.

Sandoz’s Pegfilgrastim Biosimilar Under New Review at EMA

On October 27, Sandoz announced that the European Medicines Agency has accepted its re-application for review of its biosimilar version of Neulasta® as supportive treatment in patients receiving cytotoxic chemotherapy.

PrintSandoz’s attempt to bring its biosimilar pegfilgrastim to the market was stalled in the US in Q2 2016, when the FDA issued a complete response letter. It had withdrawn its application to the European Medicines Agency in January 2017. However, the new application seems to be bolstered by additional data, according to reports.

Sandoz is expecting to reapply to the FDA in 2019, according to its website.

As noted too often in this space, the journey to approval for a pegfilgrastim biosimilar has been marked by failure and setbacks. However, as shown in the Figure from the MarketRealist, revenues for Neulasta are considerably larger than that for its nonpegylated progenitor, Neulasta (filgrastim). This is a powerful impetus for potential biosimilar manufacturers to succeed. At close to $5 billion in annual revenues, there is little reason to think that a biosimilar pegfilgrastim will not be approved eventually.

Market Realist.png

Source: The Market Realist.

In other news… AbbVie expects its Humira sales to jump to $21 billion by 2020 from $16 billion today, evidently bolstered by its successful defense of its patents against Amgen.

Evidence to Support Zarxio Use Presented at AMCP

Two posters presented at the Academy of Managed Care Pharmacy bolstered the case for moving away from the use of the originator filgrastim product Neupogen®.

In a study from Magellan Rx Management, Scottsdale, AZ, the researchers grouped both Zarxio® and Granixzarxio® together as alternatives to the originator filgrastim in the granulocyte-colony-stimulating factor (G-CSF) category as supportive oncological care. They studied the effect of a step edit, requiring the use of either Zarxio or Granix first, and its effect on utilization trends and cost savings among 2.7 million covered lives.

The step edit was implemented in October 2016 and the results for the fourth quarter of 2016 were compared with utilization and cost data from the first three quarters of that year. In terms of utilization, the marketshare of Neupogen dropped from 18% in early 2016 to only 2% by the third quarter of 2017. As expected, the drop in utilization occurred just after the step edit was introduced a year ago. The combined marketshare of Granix and Zarxio jumped from 9% to 21% over that time, but the dominant player in the G-CSF space, Neulasta® (pegfilgrastim), maintained utilization, rising from 73% to 77%. Over the one-year period since the step edit was introduced, the authors calculated a cost savings of $662,278; the cost savings in the quarter after the policy change was $106,980, or approximately 8% of the total spent for the G-CSF category.

The authors noted that the cost savings were calculated using wholesale acquisition cost (WAC) not average sales price (ASP), and manufacturer discounts or rebates were not considered in the estimates.

The second poster, sponsored by Sandoz, was a retrospective claims analysis of the incidence of febrile neutropenia in patients receiving chemotherapy who were treated with Zarxio or Neupogen. This study covered 13 months of claims (from Optum) from 162 patients taking Zarxio compared with 3,297 receiving Neupogen. The groups did not differ significantly in terms of demographics, insurance, or tumor type.

The researchers found that the incidence of neutropenia (in addition to fever and/or infection) was nonsignificantly greater in those receiving the biosimilar compared with the reference product (2.3% vs. 1.7%, respectively).

The FDA Rejects Mylan/Biocon’s Pegfilgrastim; Market Still Awaits a Biosimilar for Neulasta

In the latest blow to those seeking an alternative to Amgen’s Neulasta®, the Food and Drug Administration (FDA) sent a complete response letter to Biocon, citing manufacturing plant deficiencies, in its rejection of their biosimilar pegfilgrastim application.

Announced on October 10, this is the second biosimilar from Indian manufacturer Biocon that has been detoured by manufacturing plant problems. Its Bangalore plant, where the partners’ biosimilar trastuzumab was to be manufactured, was also cited earlier this year.

In August, Biocon and its marketing partner Mylan withdrew its European Medicines Agency applications for pegfilgrastim and trastuzumab after receiving negative reports on its manufacturing facility.

This is the second FDA biosimilar rejection relating to plant deficiencies. In June, the agency issued a complete response letter to Pfizer, resulting from a legacy Hospira plant in Kansas.

In the press release announcing the latest setback to its pegfilgrastim biosimilar, Biocon said that the complete response letter relates to “facility requalification activities post recent plant modifications. The CRL did not raise any questions on biosimilarity, pharmacokinetic/pharmacodynamic data, clinical data or immunogenicity.”

Biocon also stated that “We do not expect this [complete response letter] to impact the commercial launch timing of biosimilar pegfilgrastim in the US.” Although Mylan and Biocon had not publicly announced an intended launch date once it received approval, Amgen’s principal patents for Neulasta have expired. One might have expected a relatively quick launch of its biosimilar, considering the 180-day postlaunch exclusivity period no longer exists and the possibility of other players in the market, including Coherus, Pfizer, and Apotex (all of whom received complete response letters).

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.