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 It had withdrawn its application to the European Medicines Agency in January 2017.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.

Rituximab and Filgrastim Biosimilars Being Reviewed by FDA

Today, Sandoz announced the acceptance by the Food and Drug Administration of its application for a biosimilar rituximab. This biosimilar was approved by the European Medicines Agency in June 2017.

The manufacturer included a phase 3 trial of the agent to treat follicular lymphoma, one of two Hodgkin’s lymphomas for which the originator product is approved to treat. Its pharmacokinetic and pharmacodynamics studies were conducted in patients with rheumatoid arthritis, another major indication.

fdaThis marks the second rituximab biosimilar to be submitted to the FDA; Celltrion’s application for its Truxima™ brand was submitted in June. Sandoz’s Zarxio® has been marketed since 2015, and Erelzi® (etanercept-szzs) was approved in August 2016 but is not yet marketed.

In addition, Adello Biologic announced that their 351(k) application for a new biosimilar filgrastim was sent to FDA on September 11. No FDA decision date was announced, but assuming a smooth ride through the process, a decision may be expected around the third quarter of 2018.

This is Adello’s first biosimilar brought to FDA application. According to its website, Adello is currently in clinical trials with a pegfilgrastim biosimilar, with preclinical development on a version of adalimumab.

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.

Savvy Move or Illegal Anticompetitive Action?

Merck, which markets Remicade® in Europe, may have stepped over an anticompetitive line when Pfizer’s Inflectra® biosimilar was first made available, according to the U.K.’s Competition and Markets Authority. In the US, however, this activity would be considered routine. Certainly, nothing prevents this action and it would be fully expected, in terms of net costs.

According the UK’s Competition and Markets Authority, Merck took unfair advantage of “dominant position through a discount scheme for Remicade that was likely to restrict competition” from the biosimilar infliximab when it was launched in 2015. In this scheme, the drugmaker “unfairly” discounted the product to customers who remained loyal to the product.

Is this really different than offering rebates for preferred positioning? Anecdotal reports in the US indicate that Janssen Biotech, which markets the originator agent in North America, has taken similar action with rebates against Inflectra® (infliximab-dyyb). In fact, Amgen did the same to ward off competition from Zarxio® (filgrastim-sndz). In their cases, they did not discount the wholesale acquisition cost (WAC) to meet the biosimilars’ but simply increased the rebate to yield an equivalent net cost.

This action may be more attractive because it may have fewer implications for “best pricing” discounts required by Medicaid and other payers. Certainly, the maker of the originator product can cut their WAC costs if they desired; at the biosimilars’ modest 15% discounts, this would simply roll pricing back to 2015 levels.

In other news…A case report has been published from New York City, in which a patient switching from the reference infliximab agent to the biosimilar version experienced papulosquamous lesions a few days after the change in medication. Skin biopsy revealed the existence of a lichenoid eruption. This adverse event has not been cited previously in the literature with the reference agent Inflectra®. The direct cause of the drug reaction is unknown but further monitoring is warranted, according to the authors.

On June 2, the European Medicines Agency accepted Sandoz’s application for biosimilar infliximab and adalimumab. Sandoz has not filed a 351(k) application with the US Food and Drug Administration for either product.

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-delaythe 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.

The Coming Adalimumab Biosimilar Pricing Free-for-All

The dam wall will be broken when AbbVie’s patents on Humira® are invalidated or expired, or perhaps litigation is settled. This may happen in 2018, 2020, 2022—it is really anyone’s guess, but the one thing that is known for sure is that the day after this occurs, a quite sudden experiment in intensive competition will be underway.

There will be anywhere from 3 to 5 adalimumab biosimilars approved by the FDA when the patent fight is done. Unlike in the Hatch-Waxman Act, where there is an exclusivity period for the first generic market entrant, the BPCIA does not grant a similar benefit for the first-to-market biosimilars. And by the year 2018 or 2020, most expect the 180-day notification period to either be nullified by the Supreme Court or by Congressional legislation. In other words, there will be little restraint on competition.

Manufacturer Product Comments
Amjevita™ (adalimumab-atto)
Approved by the FDA in September 2016
Amgen believes launch in 2017 is unlikely due to patent issues
Boehringer Ingelheim
BI 695501
Filed for approval with FDA and EMA in January 2017; approval decision in Q4 2017
FDA application delayed from Q4 2016 due to manufacturing capacity issues
Phase 3 trial’s top line results reported, FDA application expected in 2017
Coherus Bioscience
Phase 3 trial’s top line results reported, FDA application expected in 2017
Samsung Bioepis
Filed with EMA in July 2016
The Merck Group (EMD Serono)
Phase 3 trials underway for plaque psoriasis (may only target this indication)

Will AbbVie remain in what is still a highly lucrative market for a drug that has paid off its research and development investment many times over? It is likely that with all of the potential players trying to keep their heads above water during the flood of competition, pricing discounts could finally be close to the dreams of payers and other purchasers (≥ 40%). This scenario depends somewhat on whether one player gambles on an early start and markets their product before patent litigation is cleared. This launch “at risk” could alter the competitive landscape. Another possible element could be AbbVie entering into an agreement with Amgen, allowing it to launch well before the others are approved. However, AbbVie’s pronouncements to date seem to be focused on fortifying the dam wall not breaching it.

The only parallel may be the moment the 6-month generic exclusivity expires, and a gaggle of manufacturers launch their products. However, we’re on a completely different level of expenditure and potential savings here. Hopefully, the dam breaks sooner than later.

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.

Are 2 Biosimilars to the Same Originator Product Biosimilar to Each Other?

In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.

We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?

What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.

Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.

First New Enbrel® Biosimilar Approved by FDA

Sandoz received approval by the Food and Drug Administration to market its biosimilar version of Enbrel® on Tuesday, August 30th. The FDA is calling this agent etanercept-szzs. It is the first biosimilar for etanercept approved for use in the US.

Sandoz has branded the product Erelzi™, and it is indicated for each of the autoimmune disorders for which the originator is approved, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and placque psoriasis.

Under current law, Sandoz could start marketing its new product 180 days after the FDA approval, which would mean a Q1 2017 launch. However, the patent litigation that has plagued many of the biosimilar agents may well delay launch of this agent. On August 11, the US District Court issued an injunction that precludes any manufacturing, distribution, or marketing efforts by Sandoz. Interestingly, Sandoz consented to the preliminary injunction. The court case associated with this patent wrangling is not scheduled to be heard until April 2017, and the decision may take some time after this. One wonders (1) how much additional revenue Amgen may rack up through the court date and (2) if Sandoz will take a much more aggressive discounting stance than it did with its first biosimilar Zarxio®.

FDA Rejects Sandoz Pegfilgrastim Biosimilar

In a stealthy move, Novartis released negative news within the bowels of a July 19th earnings report. Its subsidiary, Sandoz, received a complete response letter from the Food and Drug Administration (FDA) regarding its pegfilgrastim biosimilar application. A complete response letter is FDA’s euphemism for a formal rejection.

Sandoz is seeking to introduce its pegfilgrastim biosimilar as a competitor to Neulasta®, Amgen’s innovator product, which is indicated to prevent the development of infection in patients receiving cancer chemotherapy.

Novartis provided the news, buried as the last bullet under a section titled “Results from important clinical trials and other highlights.” The bullet reads, “Sandoz received a complete response letter from the FDA for biosimilar pegfilgrastim candidate (Neulasta®). We are working with the agency to address remaining questions.” A complete response letter means that based on the current data available, the agency has decided not to approve the drug for marketing.

Ed Silverman, an industry journalist, believes that Sandoz was issued the complete response letter in June. Unlike what you might think, FDA complete response letters are not released by the agency.

Sandoz first submitted its 351(k) filing on November 18, 2015 ( Ordinarily, an FDA Advisory Committee meeting would be scheduled to evaluate the product, but this did not happen. With other new drug filings, it sometimes means that FDA believes the original filing is missing data or clinical study information before it is ready to move forward.