Apotex/Apobiologix: Success in Canada, but Are They Shelving Biosimilars in the US?

Apotex has recently made news in Canada, introducing biosimilars and obtaining marketshare there. However, the story of Apotex and its Apobiologix biosimilar subsidiary in the US is less positive.

Apobiologix

As we’ve listed in our updated table, Apotex had originally filed for approval for its pegfilgrastim biosimilar with the FDA in late 2014 and its filgrastim biosimilar in early 2015. In 2019, no announcement has been made with regard to the filing status of either biosimilar.

In April 2018, we spoke with Apobiologix executives, who told us that the company “were still in discussions with the FDA” about the path forward for its G-CSF biosimilars. Unfortunately, this statement has not changed at all on its website. If there were discussions, they didn’t go far. And so the mystery continues.

There is some support for the view that the parent company is seeking to shed the Apobiologix subsidiary, and has been actively seeking a buyer for some time. This would make sense to a degree, as any of its newly approved biosimilars would be facing a difficult crawl to US marketshare, being the third or fourth filgrastim or pegfilgrastim biosimilar to launch.  Realizing that its marketshare potential would be substantially limited, why spend the additional developmental dollars?

In April 2018, Canada had granted the company approval to market its pegfilgrastim biosimilar (Lapelga™), and in Canada’s provincial systems, it has become a dominant player. Filgrastim was approved in Canada in 2016 (and in the EU in 2014).

According to its website, Apobiologix had been developing the following products for the US market:

  • Epoetin alfa (reference drug, Epogen®), in Phase 3
  • Darbepoetin alfa (Aranesp®), in preclinical study
  • Bevacizumab (Avastin®), in Phase 1
  • Rituximab (Rituxan®), in Phase 1
  • Trastuzumab (Herceptin®), in preclinical study

Although the pipeline lists the epoetin, bevacizumab, and rituximab biosimilars in clinical trials, no mention of any of these specific investigations can be found on www.clinicaltrials.gov, under Apotex or Apobiologix as a sponsor. A request for comment from Apobiologix was not answered by the time of this publication.

If this is the case, it is less the FDA than the parent drug maker who has lost faith in their biosimilars’ potential in the US. We can ill afford fewer active players in this market.

Senate Bill on Patents Could Turn the Purple Book Into Something More Useful

The Biologic Patent Transparency Act (BPTA), a Senate bill introduced by Senator Susan Collins (R-ME) in March, is an independent, bipartisan attempt to address patent thickets. It does so largely by clarifying an individual biologic product’s patent situation. In achieving this, it can also create a real reason for the existence of the Purple Book.

Biologic Patent Transparency Act

Today, the Purple Book is nothing more than a listing of biologic agents, their original FDA filing dates, and whether there are any biosimilars of the originator biologic. It provides very few dates when a biologic’s exclusivity period ends. One day, it may list whether a biosimilar is interchangeable with a reference drug, but there are no designated interchangeable biosimilars today (and that seems to be the case in the near future, at least).

Under the Senate BPTA proposal, the originator manufacturer must disclose all relevant patents to the Secretary of Health and Human Services. It states that “…a ‘patent required to be disclosed’ is any patent for which the holder of a biological product license approved under subsection [351](a) or (k), or a biological product application approved under section 505 of the Federal Food, Drug, and Cosmetic Act and deemed to be a license for a biological product under this section on March 23, 2020, believes a claim of patent infringement could reasonably be asserted by the holder, or by a patent owner that has granted an exclusive license to the holder with respect to the biological product that is the subject of such license…” We assume that the patent lists will be provided via the Purple Book, which is supposed to be a reference for prospective biosimilar manufacturers.

The BPTA strives to make the patents held by a manufacturer as transparent as possible. It would require drug makers to list exclusivity periods or any exclusivity extensions received, information related to interchangeability or biosimilarity of a product, approved indications, and mandates updates every 30 days. Of course, this language does not prohibit, restrict, or redress any existing patents. Any changes in the patent law is not the addressed in this proposal.

The seven bill cosponsors (as of May 2, 2019) include a group as diverse as Tim Kaine (D-VA) to Rand Paul (R-KY).

In other biosimilar news…Sandoz announced a partnership with Taiwan-based EirGenix to commercialize the latter’s investigational trastuzumab biosimilar. This agent is currently in phase III trials. Under terms of the agreement, Sandoz will market the agent globally, except for China and Taiwan.

Pfizer Receives Approval for Trazimera, the Fourth Trastuzumab Biosimilar

A fourth trastuzumab biosimilar has been approved by the US Food and Drug Administration (FDA). Pfizer’s biosimilar version of trastuzumab-qyyp (Trazimera) gained approval on March 11.

The principal phase 3 study tested Trazimera against the EU-licensed version of Herceptin®. The REFLECTIONS B327-02 study found no relevant differences in the clinical and safety outcomes for patients with HER2positive metastatic breast cancer, who also received paclitaxel. A second study tested Trazimera versus EU-licensed Herceptin in combination with docetaxel and carboplatin as neoadjuvant therapy, again demonstrating similar outcomes. The FDA’s approval covers both indications approved for Herceptin (treatment of HER2-overexpressing breast cancer and metastatic gastric/ gastroesophageal junction adenocarcinoma).

Pfizer first filed for approval of its trastuzumab biosimilar in the third quarter of 2017, and received a rejection from FDA in April 2018. Resubmission in June 2018, with additional information requested by the FDA, resulted in the current approval. The product was approved by the European Medicines Agency last year.

As with the other approved biosimilar versions of trastuzumab (Herzuma, Ogivri, and Ontruzant) in the United States, Trazimera is not yet available for prescription. Pfizer signed a licensing agreement with Herceptin’s maker Roche in December 2018, but a launch date is not yet available.

In other biosimilar news…Biocon’s biosimilar manufacturing plant has received a second citation from the FDA. The new Form 483 specified two issues, one involving sanitizing a type of barrier system and problems in tracking rejected vials.

A Profile on Lesser-Known Player in the Biosimilar Space: Nichi-Iko Pharmaceutical Company

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. 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 Japanese company, Nichi-Iko Pharmaceutical Company, Ltd.

First established in 1965, Nichi-Iko Pharmaceutical Company has been operating under its current name since 2005. It is based in Tokyo and Toyama, Japan. Historically, Nichi-Iko has produced generic pharmaceutical products for the Japanese and Asian markets. It has grown over the years through mergers and acquisitions, including the purchase of Schaumberg, Illinois–headquartered Sagent Pharmaceuticals in 2016. Sagent produces a host of generic drugs for the US market. Nichi-Iko also has a strategic alliance agreement in place with Eisai Co, Ltd.

Why you may be hearing more about this company: Nichi-Iko’s mission statement is “…to provide value-added, high-quality generic products…” but it has also ventured into the biosimilar marketplace. The company received an approval in Japan for its infliximab biosimilar (NI-071). A phase 3 trial of this product is currently being completed (completion date slated for February 2019) in US patients with rheumatoid arthritis, and the company hopes to file a 351(k) application for approval with the Food and Drug Administration later this year. Additionally, Nichi-Iko has filed for Japanese approval for its etanercept biosimilar, and is involved in a phase 1 trial for a trastuzumab biosimilar targeted for the US and EU marketplace. As the agreement with Eisai seems to apply to marketing generics only, Nichi-Iko’s subsidiary Sagent Pharmaceuticals seems to be a logical choice for biosimilar commercialization in the US.

Samsung Bioepis Scores FDA Approval of Ontruzant, the Third Biosimilar Trastuzumab

The US Food and Drug Administration (FDA) announced on January 18, 2019 the approval of a new biosimilar version of trastuzumab. Produced by Samsung Bioepis, this agent was dubbed Ontruzant (trastuzumab-dttb).

This is the third trastuzumab biosimilar approved by the FDA, following those by Mylan and Biocon in December 2017 (Ogivri®) and Teva and Celltrion last month (Herzuma®). As with biosimilars other than Herzuma and the reference biologic Herceptin®, this agent is approved for use in the treatment of HER2-overexpressing breast cancer and the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Herzuma is not approved for the latter indication.

As with Renflexis®, Samsung Bioepis’ first FDA-approved biosimilar, Merck will market the product in the US when launched. No launch date has yet been revealed.

Mylan and Biocon had signed a licensing agreement with Roche, the manufacturer of Herceptin, which ended their patent fight, but which delayed launch. Teva and Celltrion have not yet disclosed whether a similar deal has been reached with Roche. Pfizer has an investigational trastuzumab biosimilar, and they too have signed a licensing agreement with Roche.

Will the Government Shutdown Slow Biosimilar Approvals?

The partial federal government shutdown is having specific effects in various important areas of government, but it may not be particularly troubling for FDA user-fee funded activities.

Scott Gottlieb, MD, Commissioner of the FDA, has been especially busy on Twitter, trying to inform the public how the government shut down is affecting FDA operations. He made it clear that the agency is prioritizing its efforts on ensuring consumer safety.

During an extended tweet storm (the past 7 days), he has not directly addressed the effect of the shutdown on current drug approvals. However, since the pharmaceutical companies have paid into the drug approval activities of the Center for Drug Evaluation and Review, there may be sufficient funds and resources for ongoing approval activities. In a tweet last week, Dr. Gottlieb mentioned that FDA was bringing onto staff several new user-fee funded staffers. Yet, in a January 7 tweet, he promised additional information on how the shutdown would affect biosimilars; this has not yet been addressed.

In terms of biosimilars, two trastuzumab drug makers are expecting FDA decisions this quarter (Pfizer and Samsung Bioepis). However, Pfizer’s biosimilar launch is subject to a licensing agreement with Genentech (Roche), the maker of the reference product Herceptin®. Therefore, if there was a short delay in FDA approval, it will not likely have a material effect on availability for prescription. We anticipate that Pfizer will also be hearing from the FDA on its rituximab biosimilar in the second quarter.

This could raise a secondary problem with the shutdown: Will the current furlough cause a chain reaction of delays in the evaluation of existing biologic licensing applications? How long might it take the full FDA staff to catch up, if that is the case?

In a January 13 tweet, Dr. Gottlieb said, “The lapse in funding represents one of the most significant operational challenges in FDA’s recent history. But as an agency, we’re committed to fulfilling our consumer protection mandate, to the best of our abilities, under our current configuration.”

In other biosimilar news… A January 10 story in The Pink Sheet reported that Leah Christl, PhD, Associate Director of Therapeutic Biologics at FDA intends to depart the agency in the near future (a specific date was not given).

FDA Approves Celltrion and Teva’s Herceptin® Biosimilar

On December 14, the US Food and Drug Administration gave its approval for a new trastuzumab biosimilar (Herzuma™). Manufactured by Celltrion and marketed in the US by Teva, this agent has been designated trastuzumab-pkrb.

The decision marks the second trastuzumab biosimilar approval, and the 16th biosimilar agentthat has made it through the 351(k) regulatory pathway.

Herzuma was approved for a single indication: the treatment of HER2-overexpressing breast cancer. Unlike the other trastuzumab biosimilar, Ogivri®, and Herceptin, Herzuma does not carry the extrapolated indication for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

Originally submitted for approval by Celltrion in July 2017, the FDA issued a complete response letter because of plant manufacturing issues. A year later, after addressing these problems, Celltrion refiled its 351(k) application (June 2018).

Celltrion has launched Herzuma in Europe and elsewhere with marketing partners other than Teva. Neither Celltrion or Teva have announced at this time when the US launch may occur or how it will be priced. Partners Mylan and Biocon, makers of Ogivri, and Pfizer, the manufacturer of a potential competitor, have signed licensing agreements with Roche, makers of the reference product to delay launch.

Pfizer Signs Licensing Agreement With Roche on Trastuzumab Biosimilar

With Pfizer expecting to hear back on its 351(k) resubmission on a trastuzumab biosimilar in early 2019, Genentech and its parent, Roche, may have been getting nervous about their competitor’s intentions. After all, Pfizer was willing to launch at risk with its marketing of Inflectra®, the infliximab biosimilar manufactured by partner Celltrion. In fact, it is the only biosimilar manufacturer that has gambled on an at-risk biosimilar launch.

According to a report in the Pink Sheet, a district court filing on December 4 noted that the two parties signed a settlement that will put an end to their patent litigation, and presumably allow Pfizer to market its biosimilar trastuzumab in the US at a future date. As in previous agreements signed by Roche, the terms are confidential, and launch dates and licensing fees are unknown.

trastuzumab biosimilar

A similar confidential agreement was completed between Mylan and Roche, for Mylan and partner Biocon’s Ogivri®, the first trastuzumab biosimilar approved by the Food and Drug Administration (FDA) in April 2017.

Three other trastuzumab biosimilars are also trying to reach the market. Amgen and Allergan received a complete response letter in June 2018, and have not yet announced when it might resubmit its 351(k) application. Samsung Bioepis is awaiting its initial decision on its trastuzumab biosimilar, filed in January 2018. Teva and Celltrion seem to be on the cusp of an FDA decision, after receiving their initial rejection in July 2017.

Roche has it covered, though. It filed patient litigation against Samsung Bioepis in September 2018 and partners Celltrion and Teva as well.

This is the very situation that the federal government, payers, and patients want to try to avoid, however. Licensing fees paid to the reference manufacturers may work to significantly inflate the drug’s price to the health system. The lack of transparency characterizing these agreements and the associated delays in launch are being decried by those patients and entities who can benefit from access to biosimilar competition. Herceptin was first approved in 1998. No one envisioned Genentech having 20+ years of marketing exclusivity.

In other biosimilarnews… MomentaPharmaceuticals, which signed an Abbvie licensing agreement for its biosimilar adalimumab, said in a statement that it will delay FDA filing M923 beyond 2019, which will help reduce its corporate expenditures. This delay should not impact the expected commercial launch date of November 20, 2023, according to the company.

Celltrion announced that it has filed an application for European Medicines Agency approval for its subcutaneous form of its infliximab biosimilar Remsima (US brand name, Inflectra®). This would provide the first subcutaneous injection formulation of infliximab.

An FDA Filing for Momenta’s Adalimumab Biosimilar Coming Soon?

Momenta seems to be in final preparations for its first 351(k) filing to the Food and Drug Administration (FDA). In its recent investor conference, the company disclosed that it is ready to send M923, its adalimumab biosimilar, to the agency for approval.

Momenta's Adalimumab Biosimilar
Craig Wheeler, CEO of Momenta Pharmaceuticals

Despite this promising news, Momenta is facing strong headwinds. Even if it gains approval, Momenta expects that the US launch of the adalimumab biosimilar will not occur until 2023, owing to pending patent issues with Abbvie’s Humira®. The company does not yet have a marketing partner for this agent, though there appears to be plenty of time.

In addition, Momenta received a setback in November 2017 on another looming biosimilar candidate, when its biosimilar version of abatacept failed its phase 1 trial. Apparently, its M834 produced pharmacokinetic results that differed from the originator Orencia® in this early clinical study. Momenta is still studying the data and trying to come to grips with the surprising findings.

The company is also set to begin “pivotal” clinical trials on its other drug candidate M710, a biosimilar to aflibercept. The originator product is Eylea®, and it is indicated to treat wet age-related macular degeneration.

Momenta’s partnership with Mylan is moving forward with preclinical work on four other nonspecified biosimilars, according to the company. But all of this development costs money, and Momenta has acknowledged that it may need to raise cash for future development.

Momenta received approval in January for a generic form of the multiple sclerosis drug Copaxone® (glatiramer acetate). The approval of this agent, produced in partnership with Sandoz, had been delayed because of manufacturing issues. The company recognizes that the entry of Mylan (ironically) into this market may hinder its financial outlook.

As a result of these developments, Momenta stated it would entertain a sale of its adalimumab biosimilar “or other assets.”

 

The Patent Games: Another Sequel Underway

Roche/Genentech has filed suit in Delaware, citing the alleged violation of 37 patents by Amgen in its intent to market its biosimilar version of Herceptin®.  

The litigation was filed in response to Amgen’s stated intention of launching their product in October 2018, based on a May approval. Unfortunately, the Food and Drug Administration decided not to approve Amgen and Allergan’s initial 351(k) application in early June.

Roche has been engaged with Pfizer and the team of Celltrion and Teva on their trastuzumab biosimilars as well.

FDA Approval Eludes Amgen for Biosimilar Trastuzumab

Amgen will have to wait a bit longer to market its biosimilar version of trastuzumab . On Friday, June 1, the Food and Drug Administration (FDA) rejected Amgen’s 351(k) application for its Herceptin® biosimilar. biosimilar trastuzumab approvalIn a brief press release, Amgen announced receiving the complete response letter for ABP 980. In the announcement, it also said that the delay in its biosimilar trastuzumab approval should not “impact our US launch plan.” This may signal that even if it received approval, it would not market the biosimilar trastuzumab immediately.

The timing of the FDA announcement on the biosimilar trastuzumab approval contrasted with the near-simultaneous marketing authorization of this same trastuzumab biosimilar by the European Medicines Agency. The biologic will be marketed in Europe under the trade name Kanjinti™.

Mylan/Biocon’s Ogivri™ remains the only biosimilar trastuzumab approved by the FDA. It is not yet marketed, however. Separate trastuzumab biosimilars by Teva/Celltrion and Pfizer have been stalled by the FDA. Samsung Bioepis’s entry is due for an FDA approval decision in the fourth quarter of 2018.

In related biosimilar news… in September 2017, Mylan filed a 505(b)2 application for its insulin glargine agent. The manufacturing duo of Mylan and Biocon received a rejection from the FDA on June 1. The complete response letter specified issues raised by a change in manufacturing site (from one in India to a new facility in Malaysia). As reported by the Economic Times, the complete response letter was expected by Mylan and Biocon. They told the Economic Times, “Together, Mylan and Biocon are already executing on all required activities we had agreed upon with the FDA, and they are progressing according to plan,” the statement said.

Although insulins are not currently approved through the 351(k) biosimilar pathway, they are among the “transitional agents,” which by 2020 will be considered biosimilars by the FDA.