FDA Advisory Committee Unanimously Recommends Approval for Avastin® and Herceptin® Biosimilars

It was a good day for biosimilar manufacturers and a bad day for Roche and its Genentech unit. Following a broadly positive FDA staff review of the first products to directly treat tumors, the Food and Drug Administration’s Oncology Drug Advisory Committee took the expected step of unanimously recommending approval for agents from Amgen and Mylan.

In the morning session, Amgen and Allergan’s ABP-215 was convincingly presented as equivalent to Roche’s bevacizumab (Avastin^®), based on pharmacologic, pharmacokinetic, efficacy, and safety evaluations. Clinical studies were performed in patients with non–small cell lung cancer. The Advisory Committee voted 17-0, recommending approval of the drug for all of the originator product’s nonprotected indications:

As first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy
Combined with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line ABP 215-containing regimen
As first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non–small cell lung cancer in combination with carboplatin and paclitaxel
For the treatment of glioblastoma with progressive disease in adult patients following previous therapy as a single agent
For the treatment of metastatic renal-cell carcinoma in combination with interferon alfa
In combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix

Several questions brought up by the Committee involved the glioblastoma indication, and the drug’s passage over the blood–brain barrier. Progressive multifocal leukoencephalopathy was also mentioned, but this did not deter the Committee from its unanimous vote.

Amgen did not apply for approval for Avastin’s other orphan indications, which are “protected,” according to FDA. If they did want to obtain approval for those, an additional data package would need to be submitted.

Immunogenicity studies did not reveal any material differences between the biosimilar and originator product. In a minor twist, Amgen did the clinical testing of its biosimilar against the EU-licensed version of Avastin, and it had to conduct bridging studies to demonstrate the similarity between the EU version and the US-licensed originator drug.

In the day’s second session, Mylan’s MYL-1401O, a biosimilar version of Roche’s Herceptin (trastuzumab), was evaluated. The totality of evidence, according to the FDA staff review documents, supported the 351(k) application by Mylan. The Advisory Committee agreed, voting 16-0 to recommend the biosimilar for approval for use in Herceptin’s indications:

For use as adjuvant treatment of HER2 overexpressing node- positive or node-negative (ER/PR negative or with one high risk feature) breast cancer (1) as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; (2) with docetaxel and carboplatin; or (3) as a single agent following multimodality anthracycline-based therapy
In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
In combination with cisplatin and capecitabine or 5- fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

The FDA usually accepts the recommendation of its Advisory Committees in issuing final decisions. However, in late June, the agency rejected Pfizer’s Retacrit despite a 14–1 Advisory Committee vote to recommend, based on potential problems at a manufacturing facility. Mylan’s manufacturing partner Biocon, has recently been cited by French inspectors in connection with its European approval application, for potential problems at its Bangalore plant.

A final FDA decision is expected for Amgen’s bevacizumab biosimilar by September 14, and for Mylan’s trastuzumab biosimilar by September 3.

Pegfilgrastim: 0 for 3 on Biosimilars at FDA

On June 12, Coherus Biosciences received word of the Food and Drug Administration’s (FDA’s) rejection of its biosimilar pegfilgrastim. Manufacturers have now taken 3 swings and misses, striking out in their quest for a biosimilar version of another blockbuster product.

In 2016, Sandoz whiffed on its version, after having the nonpegylated version approved in 2015 (Zarxio^®). Although details of the FDA’s complete response letter were not released, Sandoz decided to withdraw its application to the European Medicines Agency as well. In December 2014, Apotex was the first to submit its pegfilgrastim application to the FDA, but it was similarly rejected.

The remaining biosimilar version of Neulasta^® awaiting its turn at bat in the US is from Mylan/Biocon. Submitted in February of this year, the FDA decision is due October 9, 2017. Pfizer is working on its own version of pegfilgrastim (HSP-130), which is in phase 2 study. Apotex’s Apobiologix unit is still seeking approval of its biosimilar, according to its website. In Europe, 2 pegfilgrastim applications are currently awaiting decisions, but none have been approved to date. Image result for pegfilgrastim (neulasta)

On the bright side, the FDA’s complete response letter to Coherus did not indicate that the game is over. Apparently, the agency asked for a re-analysis of specific data and requested further information regarding manufacturing its biosimilar agent. The drug maker indicated its willingness to work with FDA to resolve these concerns.

There seems to be something about the pegylated version of filgrastim that makes it more difficult to obtain an approval during the first plate appearance. It may well be that Mylan’s application hits it out of the park in October. However, the batting average of drug makers pitching their other biosimilars is far better—Pfizer’s second try at approving epoetin seems to have been a hit (with a 14-1 margin by the FDA Advisory Committee).

With $4.5 billion in US sales of Neulasta last year, there will be no shortage of hitters willing to come to the plate.

Frustration Mounts as Sandoz’s Etanercept Biosimilar Launch Delayed into 2018

Call it irritation, exasperation, or frustration, but biosimilar manufacturers and payers alike are feeling it, as the fight over drug patents has barred the way to approval for yet another biosimilar for a costly biologic.

In this case, Sandoz’s Erelzi™, which was approved by the Food and Drug Administration on August 30, 2016, has been caught in the patent litigation web. The originator drug, Amgen’s Enbrel^® was first approved in 1998. Amgen asserts that its patent on the agent protects exclusivity until 2029, which would give Amgen 31 years of sole marketing rights. Despite the unlikely event that it can defend its patent for this extraordinary period, Sandoz has acknowledged that it will need to hold off launch of the biosimilar until at least 2018.

In a report from Reuters on January 25, Richard Francis, CEO of Sandoz, stated that the legal battle “won’t really reach a conclusion until 2018. That’s the frustration sometimes of the legal situation, but the way I look at that, we’re carving the landscape out as we go.”

Indeed, Sandoz has been at launch-delay the forefront of legal battles, also fighting Amgen on the validity of the 180-day notification period, which is now being readied for US Supreme Court arguments in the Spring. The 180-day notification period for Erelzi was due to end in
late February 2017. After this time, Sandoz may still launch the product, at risk of financial penalties and loss of revenues, if the courts rule that Amgen’s remaining patent is valid.

However, the potential for savings on Enbrel, through biosimilar competition, continues to be a mirage for payers. The agent, which pulled in US revenues of $5 billion in 2015, has been the subject of numerous recent price increases. Health plans and insurers, while believing these costs untenable, may have little choice but to pay up or find ways to more aggressively restrict access.

Supreme Court to Hear Sandoz v. Amgen Arguments on the 180-Day Notification Period

It seems that the Supreme Court will in fact hear Novartis’ case in an attempt to overturn the 180-day notification period, as part of the “patent dance.” Its biosimilar-making subsidiary (Sandoz) will finally get its day in the nation’s top court in April, with a decision expected sometime in July.

The announcement has taken many by surprise because of an announcement by the court in December that it would not hear a similar case involving Apotex v. Amgen.

Although any new decision by the Supreme Court will have no bearing on the circumstances of the original case—Sandoz launched in September 2015 after sitting out the 180-day notification period—it will have important ramifications for biosimilars coming to market in the future. It is widely viewed that this notification is wholly unnecessary. This mandate of the BPCIA was intended to allow the completion of patent litigation, but instead is seen as an extension of the originator product’s exclusivity period.

However, even if the Supreme Court rules to strike down this unintended additional period of exclusivity, it may have relatively little effect in getting biosimilar products to the market sooner. Instead, the remaining patent litigation will prevent most drug makers from a quick launch after receiving Food and Drug Administration approval.