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Pharmaceutical companies usually do their utmost to extend the patent protection period to prevent the listing of generic drugs in order to gain market exclusive rights. Fiercepharma recently released a list of TOP10 drugs that lost exclusive rights in the United States in 2019, listing 10 varieties from seven pharmaceutical companies, among which the highest sales in the US reached $4.29 billion.

Judging from the sales revenue in previous years, the most affected company is the cancer drug giant Roche. The three major monoclonal antibodies Rituxan, Herceptin, and Avastin, which contributed huge cash flow to them, faced the competitive challenge of listing biosimilars in the US in 2019, but it remains to be seen how much biosimilars can make a difference.

Unlike other breeds that come from external challenges, Gilead has broken its own arms and launched the authorized generics of hepatitis C drugs Epclusa and Harvoni. In addition to the two hepatitis C drugs, the Gilead pulmonary hypertension drug Letairis will also lose its exclusive rights in the United States, but these competitors have not yet appeared. Its angina drug Ranexa is also likely to face new challenges in 2019.

 

NO.1 Rituxan (rituximab)

Rituximab is a human-mouse chimeric anti-CD20 monoclonal antibody that binds to CD20 on B lymphocytes and initiates an immune response to B cell lysis. Rituxan was first approved in the United States in 1997, and treatable indications include follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.

Roche originally expected Rituxan to greet generics in 2018, but until November 28, 2018, the FDA approved Truxima (rituximab-abbs), the first rituximab analog Celltrion/Teva developed. Specific time to market, but the specific time to market has not been disclosed. Since the time-to-market and the degree of substitution of generic drugs cannot be accurately predicted, Roche has not made specific expectations for Rituxan’s decline in sales in the United States.

However, from the Roche financial report in 2018, it is obvious that the impact of the listing of biosimilar drugs on the original research products. The variety’s revenue in 2018 was US$6.81 billion, of which US growth was 4%, and Europe’s impact sales of biosimilars fell 47%.

 

NO.2 Lyrica (Pripalin)

Pregabalin is an analog of the neurotransmitter gamma-aminobutyric acid (GABA), and FDA-approved indications include diabetic peripheral neuralgia and post-herpetic neuralgia (2004/12/30), local epileptic seizures ( 2005/6/10), fibromyalgia (2007/6/21), neuropathic pain associated with spinal cord injury (2012/6/20). According to data provided by Evaluate, since the FDA approved the drug, the drug has generated more than $30 billion in sales in the United States.

Pregabalin’s compound patent and pain indication patents will expire on 2018/12/30. But after testing in pediatric patients, Pfizer received another six months of market exclusive rights from the FDA until June 30, 2019. Teva, Mylan, Sandoz and other companies have submitted generic applications. According to patent informed sources, the compound patent of pregabalin is still in the protection period and has not entered China; the use of the compound for the treatment of pain expires and expires.

Although Pfizer faces billions of dollars in revenue losses due to the expiration of the Lyrica patent. However, the company currently adopts a parallel strategy of “original research + imitation”. Especially in the imitation of biological products, Pfizer is at the forefront of multinational pharmaceutical companies. For example, the company launched the first biosimilar drug of Remicade (original Johnson & Johnson) as early as 2017, and in 2018 launched the biosimilar of Recrit/Epogen’s erythropoiesis stimulant Retacrit. Dr. Mikael Dolsten, the company’s president of research and development, is even more vocal on the 2019JP Morgan. Pfizer holds four “high-value biosimilars” with the potential to be approved.

Although the biosimilar market in the United States is still in the incubation stage compared to the European Union, it has to be acknowledged that Pfizer has played a positive role in promoting the development of generic drugs. I still remember that the former FDA director had angered the original company to prevent patients from choosing generic drugs in order to protect profits with various “intimidation”?

On November 30 last year, Pfizer announced a settlement with AbbVie on the worldwide patent litigation of adalimumab biosimilars. Under the agreement, in the European market, Pfizer’s adalimumab biosimilars will be available for sale upon approval by the EMA. However, in the US market, Pfizer is required to market adalimumab biosimilars on or after November 20, 2023.

 

NO.3 Herceptin (trastuzumab)

Trastuzumab, one of the Roche troikas, has contributed more than $100 billion in revenue to Roche since its launch. Roche’s 2018 earnings report revealed that Herceptin’s sales fell 16%. At present, three kinds of trastuzumab biosimilar drugs have been approved by the FDA, and the variety will be lost on June 18 this year, which is a crisis.

However, Roche seems to have prepared for Herceptin’s biosimilar drug competition. In the fifth year after Herceptin’s launch (2013), Kadcyla, an antibody conjugate targeting HER2, was marketed. However, the drug has been on the market for many years, sales have not reached Roche’s expectations, and sales in 2018 are less than 1 billion Swiss francs. However, Roche still hopes that Kadcyla will take over the responsibility of Herceptin and increase market share by expanding indications. The early breast cancer data released at the beginning of the year proved this.

 

NO.4 Avastin (bevacizumab)

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) developed by Roche. It was approved by the FDA and EMA on February 26, 2004 and January 12, 2005.

So far, the United States has only approved a bevacizumab-like biosimilar drug, which approved Mvasi (bevacizumab-awwb) jointly developed by Amgen and Allergan on 2017/9/24, and Pfizer, Samsung and Celltrion are also Avastin is a competitor of imitation products. However, due to the incomplete resolution of patents between Amgen and Roche, the pricing and time-to-market of Mvasi in the US market has not yet been determined.

Due to the large growth pressure of its three best-selling products, Roche hopes that the newly approved drugs in recent years can create new sales. The main drugs include multiple sclerosis Octrevus, hemophilia drug Hemlibra, new influenza drug Xofluza, and a new generation of anticancer drugs Perjeta and Kadcyla, and even PD-L1 immunotherapy Tecentriq.

 

NO.5 Epclusa, Harvoni

Due to the high rebates and tough payers, Gilead has a difficult situation with its hepatitis C drugs, including the full-genotype treatment of Epclusa and the once-high flying Harvoni. In response, the company made a striking move – choosing to launch its own generics within a few years of FDA approval.

According to Evaluate, Epclusa received FDA approval in 2016 and has generated nearly $9 billion in the US so far. In 2018, Epclusa’s sales revenue in the United States was $934 million. Harvoni went public in 2015 and reached sales of $13.86 billion the following year. With the cure of hepatitis C, the sales of the drug continued to decline. By 2018, the annual sales were only 1.22 billion US dollars, of which the US sales revenue was 802 million US dollars.

Gilead is responding to this situation with an unusual solution. The company formed a subsidiary called Asegua Therapeutics to launch generics for Epclusa and Harvoni for $24,000 per product. Because the price of its hepatitis C drug has dropped by 60% in recent years, the price of generic drugs is not much cheaper than the original one, but the company’s senior executives hope to increase sales by increasing sales.

Due to the sharp decline in hepatitis C drugs, Gilead had to seek other growth. For example, in 2017, the company acquired the kite pharmaceutical company for $12 billion and acquired its CAR-T drug Yescarta, which generated $264 million in revenue in 2018. On March 1 this year, Dan O’Day, the former CEO of Roche Pharmaceuticals, served as the company’s CEO, which is seen as a signal that Gilead will seek expansion of oncology.

 

NO.6 Sensipar (Cinacasace)

Sensipar is a calcium-sensitive receptor agonist whose core patent has expired in March 2018, but due to the difficulty of imitation, there are still very few generic drugs on the market. In 2018, Sensipar’s sales in the US fell to $1.43 billion. At present, Amgen is actively responding to generic drug shocks, such as patent litigation for some generic drug companies.

According to the FDA Orange Book, other Sensipar patents will expire in 2026. In the 2018 financial report, Amgen has taken into account the impact of the 2019 imitation version of Sensipar on its performance. The report said that the possibility of generic products appearing after the fourth quarter of this year is 40%.

In addition to Sensipar, the company Neulasta, Epogen and Enbrel are also facing biosimilar competition. Novartis’s Enbrel biosimilar has been approved by the FDA under the trade name Erelzi. Amgen recently said that the lawsuit against the Enbrel patent will take some time to complete, so it is not clear when the generic product will enter the market.

 

NO.7 Advair (fluticasone propionate salmeterol)

GSK’s Advair eventually encountered competition in generics. Wixela Inhub (fluticasone/salmeterol) developed by Mylan is Advair’s first generic drug, which was approved by the FDA on 2019/1/30 and officially launched on 2019/2/12.

In fact, GSK lost the patent protection of the drug as early as 2010. However, because of the lack of generic intervention, the product still generated sales of 5.27 billion pounds for GSK in 2013 and 2.4 billion pounds in 2018.

The reason why the patent expired for many years has not been the listing of generic drugs, in part because the Diskus inhaler technology is difficult to replicate, and the device itself did not lose intellectual property before 2016. Even after the last patent expired, many generic drug manufacturers are still struggling to get their products through FDA review.

Before being approved in January this year, Mylan also experienced many FDA refusals and extensions. In 2018, the FDA rejected copies of the partners from Hikma and Vectura, asking them to supplement clinical research. Novartis recently said that it is expected to launch a generic product of this variety in 2020.

After Wixela Inhub went public, an analyst predicted that it would bring nearly $250 million in sales to Mylan this year, but another analyst expects only $170 million.

 

NO.8 Restasis (Cyclosporine)

In 2017, in order to protect the patent of Restasis, Allergan transferred the Restasis patent to the Native American tribe of St. Regis Mohawk, and then re-licensed Allergan exclusively through the tribe. This kind of trick has caused the company to be criticized, and market observers quickly said that it has had a negative impact on the industry as drug pricing became the headline news.

According to a lawsuit filed by four chain pharmacies last year, Teva, Melan, Amneal and several other generic drug manufacturers wanted to share the brand’s sales. The retail pharmacy sued Allergan for an “illegal plan” to protect Restasis, saying the company continued to protect the patents that were due to expire through “missing statements.” The plaintiff said that generic drugs could be launched as early as May 2014, not because of misrepresentations and Allergan’s actions.

Even though the strategy was under review, Allergan continued to defend himself, but suffered a series of failed lawsuits. For example, Mylan won the case in the federal court case, invalidating the Restasis patent. Even if the lawsuit is won, it is difficult for generic manufacturers to ensure that the FDA will approve generic drugs. However, this situation may change soon, it is reported that the FDA ruled that the date of Mylan generics is coming, and is likely to be approved.

The drug contributed $1.2 billion in sales to Allergan in 2018.

 

NO.9 Letairis (Ambergen)

The important patent for Letairis expires this year and the drug was approved in 2007 for the treatment of pulmonary hypertension (PAH). Since the expiration of a patent last year, Gilead has been preparing for the competition, but so far, generic manufacturers have not yet “broken into the door.”

Letairis has been one of Gilead’s important sales sources, with revenue of $943 million in the US last year. Even though Gilead has prepared for the competition, the situation is not optimistic. In order to cope with future competition, Gilead has been paying high rebates to ensure the number of prescriptions.

Letairis, Epclusa and Harvoni are not all the branded products that Gilead needs to meet the generics challenge this year. Its angina drug Ranexa (ranolazine, ranolazine) also lost its exclusive right to the market. Last year, its market revenue in the United States reached $758 million.

As mentioned earlier, Gilead is reborn by acquiring and replacing CEOs. Yescarta’s $266 million revenue in 2018 is far from enough to compensate for the loss of performance. According to informed sources, the medical use of Letaris for the treatment of PAH is still under the protection period and has not entered China.

 

NO.10 Suboxone film (buprenorphine + naloxone)

UK-based Indivior had Suboxone sales in the US last year at $790 million, most of which came from Suboxone film. This product is used to treat patients with opioid addiction, because early tablets have encountered competition in generics, and film has become the cornerstone of Indivior’s business. Now, Suboxone film has also faced generic impact.

In early March, Indivior failed in a lawsuit to stop Suboxone film. In the case of Indivior holding a paper ban, Indian pharmaceutical company Dr. Reddy “adventure” to launch its generics. The US Court of Appeals for the Federal Circuit abolished the ban and vetoed Indivior’s request for reconsideration in early February.

Although Indivior said it plans to file a complaint with the Supreme Court. But with legal efforts, several generic companies have listed their products one after another, and Indivior has also launched its own authorized generics. Indivior has now developed a “contingency plan” to deal with lost sales. The company hopes to focus its spending on Sublocade and its new schizophrenia drug, Perseris (risperidone, risperidone long-acting injection).

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