High-end complex preparations: hard bones, huge rewards

High-end complex preparation series: In the face of the real know-how, can make a drug on the market for 20 to 30 years, the annual sales can be maintained at more than 1 billion US dollars all year round, even if the halfway patent expires, it is difficult for generic drug manufacturers to follow, and the threshold and return of highly complex preparations are so high

1 Introduction

Any pharmaceutical company hopes that the drugs they develop belong to the varieties with large market space, small competitive space and perennial high profits, such varieties at first glance do not seem to exist in this world, but with one more qualifier, the threshold is high, such varieties have a reason for existence, and high-end complex preparations belong to such varieties

From the perspective of the original research and generic drugs, this paper introduces the high-end complex preparations that have a high threshold and can maintain high profit margins all year round, and divide them into 3 categories, "late imitation", "difficult imitation" and "can not be imitated", all of which reveal the huge investment value

"Late imitation", after the expiration of the original research patent of the large variety of ordinary preparations, many generic drugs will be born in one or two years, making the sales of the original research show a cliff-like decline, while for high-end complex preparations, after the expiration of the patent, it will take many years for the sporadic appearance of generic drugs, and the impact on the original research sales is limited

"Difficult to imitate", many years after the expiration of patents for high-end complex formulations, there is still no generic drugs, and even THE FDA funds certain institutions to help the development

"Can not be imitated", due to the difference in patent examination between China and the United States, the original research in the United States patents are still within the scope of protection, and the patents in China have expired, so that domestic capable pharmaceutical manufacturers will develop high-end complex preparations earlier, while foreign original research is still expanding indications, which is an incremental market

2 Late imitation

Doxorubicin hydrochloride liposome injection

Doxorubicin belongs to the anthracycline class of drugs, anthracycline drugs have become one

A 2012 clinical trial meta-analysis article looked at 2220 patients, of whom 1112 received liposomal anthracyclines and 1108 received conventional anthracyclines, showing that doxorubicin liposomes have better cardiac safety and less bone marrow suppression, hair loss, nausea and vomiting, and have a better therapeutic index without affecting efficacy (data 1

Comparing the difficulty of process development between the two, it takes 2 years for ordinary injections to appear at least 3 generic drugs, while liposome injections take 8 years

Figure 1 FDA approved varieties of doxorubicin hydrochloride injection over the years (red represents delisting, source: FDA, compiled by Fengshuo Venture Capital)

Figure 2 VARIETIES OF DOXOBICIN HYDROCHLORIDE LIPOSOME INJECTION APPROVED BY THE FDA OVER THE YEARS (Source: FDA, compiled by Fengshuo Venture Capital)

Amphotericin B liposome injection

Traditional amphotericin B is a broad-spectrum antifungal drug that has been used as the standard therapy

Amphotericin B liposome injection, the trade name AMBISOME, was approved by the US FDA in 1997, looking through Gilead's annual reports over the years, AMBISOME's global sales from 1998 to 2021 showed an overall upward trend, reaching $540 million in 2021, according to the market division, the drug in the United States market is not large, perennial sales in the tens of millions of dollars, revenue contributions mainly from the European market and the rest of the market

The drug has not yet reached its peak after 25 years on the market and is currently maintaining a good growth rate, with a year-on-year increase of 19%

Figure 3 AMBISOME over the years, $100 million (Source: Gilead Annual Report, compiled by Harvest Venture Capital)

Goserelin acetate extended-release implant

Goserelin is a decapeptide analogue of luteinizing hormone-releasing hormone (LHRH), which is made into a subcutaneous implant of 1-month preparation and 3-month preparation by dispersing it in biodegradable propylide/ethylenecarpent copolymer, mainly for the treatment of

ZOLADEX, the trade name ZOLADEX goserelin acetate sustained-release implant in 1989 was approved by the US FDA, looking through AstraZeneca's annual reports over the years, ZOLADEX's global sales from 2001 to 2021 have fluctuated slightly overall, but in recent years have maintained sustained growth, reaching $948 million in 2021, according to the market division, the current market for this drug in the United States is not large, sales in the tens of millions of dollars, revenue contributions mainly from emerging markets

The drug peaked in 2011 and peaked at $

Figure 4 ZOLADEX over the years, sales, billions of dollars (Source: AstraZeneca Annual Report, Compiled by Harvest Venture Capital)

Octreotide microspheres for injection

Octreotide is a synthetic cyclic octapeptide derivative with pharmacological properties

The octreotide microspheres for injection named SANDOSTATIN LAR were approved by the US FDA in 1998, and the annual reports of Novartis over the years were roughly obtained as follows, the first point is that the daily injection form of SANDOSTATIN appeared in the first 3 generic drugs only 2 years, the patent expiration time outside the US region of the January preparation was 2010, until 9 years later in 2019 in Europe, the patent expiration time in the United States was 2014, There will still be no generic drugs
by 2022.

Figure 5 Fda approved daily preparation varieties of octreotide for injection over the years (red represents delisting, source: FDA, fengshuo venture capital collation)

The second point is that the dosage form of daily injection has been sold for nearly 20 years since its listing in 1988, and its sales have not exceeded the $1 billion mark until January 1998, after the microspheres of the preparation were listed, the amount was increased year by year, and in 2007, this variety (daily + January) finally reached the $1 billion mark, when the daily preparation has more than 3 generic drugs listed, and in the following year or two the annual report was confirmed, 90% of the sales contribution of this variety came from the January preparation
.
So the figure below can almost be considered as the sales revenue
of the January formulation SANDOSTATIN LAR.

Figure 6 SANDOSTATIN sales over the years, $100 million (Source: Novartis Annual Report, compiled by Harvest Venture Capital)

The third point is that this variety contributes more than half of sales
to the U.
S.
market all year round.

In summary, for this variety, long-acting preparations can not only well avoid the sales of generic drugs on ordinary dosage forms, but also create new sales highs, high-end preparations of high-tech thresholds, greatly delaying the entry of later imitators, so that it remains at the sales level
of more than one billion DOLLARs all year round.

Lanripeptide acetate extended-release injection

Lanray peptide has a similar mechanism of action to octreotide, both are octapeptide derivatives of natural somatostatin, and lanrui peptide sustained release injection is a gelatinous January preparation
.

The trade name somatuline DEPOT of Lanritide acetate sustained release injection was approved by the US FDA in 2007, check ipsen annual report over the years, SOMATULINE sales have increased year after year, is a billion euros of varieties, in recent years by the European region octreotide (began in 2019) and Lanray peptide (began in 2021 Germany, German patent expired in 2015) generic drugs, resulting in a slowdown in growth, the main market concentrated in the United States, The U.
S.
regional patent expires in 2020, and there are no generic drugs
so far.

Figure 7 SOMATULINE DEPOT over the years, billions of euros (Source: IPSEN Annual Report, compiled by Fengshuo Venture Capital)

3 Difficult to imitate

Risperidone microspheres for injection

Risperidone is an atypical antipsychotic drug, initially in a daily oral dosage form, but in mental illness, one of the key factors affecting the clinical effectiveness of the drug is compliance, and later developed injectable risperidone microspheres (2-week preparation).

As can be seen from the following 3 figures, the oral dosage form of risperidone with low manufacturing threshold will flock out once the patent expires, and the sales of oral dosage forms will fall from $2.
126 billion in 2008 to $899 million in 2009, a one-year decline of 57.
71%.

Figure 8 Oral dosage form varieties of risperidone approved by the FDA over the years (red represents delisting, source: FDA, compiled by Fengshuo Venture Capital)

Risperidone microspheres were approved by the U.
S.
FDA in 2003, and the full dosage form (daily oral + long-acting microspheres) peaked at $
4.
183 billion in 2006.
After the oral risperidone patent cliff in 2009, the risperidone microspheres successfully took over the baton, and in 2011 the risperidone microspheres reached a sales peak
of $1.
583 billion.
Sales fell later, partly due to stiff competition from cheap oral dosage forms and strong sales of Johnson & Johnson's own other long-acting antipsychotic drug, paliperidone
.
As for the clinical effects of these several long-acting antipsychotics (aripiprazole, olanzapine, paliperidone, risperidone, etc.
), a 2017 study (data 5) showed little difference
in effect between them.

Therefore, risperidone microspheres still have considerable clinical value, and in the face of the erosion of oral generic drugs for more than a decade, its sales in 2021 are 592 million US dollars, which is still a big variety
.
Its U.
S.
patent expires in 2020 at the latest, and there is still no generic drug, which is a strong contrast with the oral generic drug of the crowd, highlighting the high technical threshold of microspheres
.

Figure 9 Risperidone has been sold over the years, using $100 million (Source: Johnson & Johnson Annual Report, Compiled by Harvest Venture Capital)

On the other hand, INDIVIOR took the path of improved new drug development, according to the Orange Book, the earliest patent application number was 10010612, the application time was 2008, the drug candidate at that time was RBO-7000, according to the clinical trials registration time, the earliest in 2012 into the clinical trial stage, until 2018 was approved by the FDA, sales in 2021 were $17 million (an increase of 21% year-on-year).

。 Perseris is a drug that has been improved in two main places, from a 2-week formulation to a 1-month formulation, and does not require the recommended loading dose and oral supplementation of risperidone
.

Spending so much time and money and energy, just achieving such sales results, perhaps the original path of high-end generic drugs will have different results, after all, when the efficacy has not made a revolutionary breakthrough, it is difficult to compete with
mature and established drugs.
At the same time, we cannot ignore that in the case of the same active ingredient, it is much easier to make PD equivalent than PK equivalent, which does not also illustrate the high imitation threshold of high-end preparation varieties
.

Long-acting olanzapine injection

Olanzapine, similar to risperidone, is an atypical antipsychotic drug that initially came in a daily formulation and was followed by the development of a long-acting olanzapine injection (a January formulation
).

As can be seen from the following 3 figures, the daily dosage form of olanzapine with a low manufacturing threshold will flock out
once the patent expires.

Figure 10 Olanzapine daily dosage form varieties approved by the FDA over the years (red represents delisting, source: FDA, compiled by Fengshuo Venture Capital)

The long-acting olanzapine injection (January formulation) was approved by the U.
S.
FDA in 2009, and the following year in 2010, the entire olanzapine cultivar reached a historical peak of $5,026.
4 million, and the sales contribution at this time was mainly from the daily formulation
of olanzapine.
Later, due to the patent cliff of olanzapine daily preparations, in the face of the above-mentioned swarming generic competitors, the sales of all-dosage forms of olanzapine fell from US$4.
622 billion in 2011 to US$1.
7014 billion in 2012, a decline of 63.
19%.


。

Although Eli Lilly has never separately announced the sales of long-acting olanzapine injections, from the perspective of sales of the whole dosage form, long-acting olanzapine injections do not complete the handover stick well, allowing sales to complete the secondary increase, which is largely due to the fact that long-acting olanzapine injections have a unique and rare post-injection delirium sedation syndrome, limiting their expanded use
.

However, from the perspective of stable sales in recent years, and achieving year-on-year growth for the first time in 2021 (after 2011), stable at about 400 million to 500 million US dollars, it is enough to prove the clinical value of long-acting olanzapine injections (based on more than a dozen generic olanzapine daily preparations of generic drug competitors, inferred that sales at this time are mainly from long-acting olanzapine injections that do not yet have generic competitors), possibly based on their comparison with risperidone microspheres, do not require oral supplements, compared with oral olanzapine, metabolic effects (weight gain, Lipid abnormalities, glucose imbalance) is lighter
.

Figure 11 Olanzapine full dosage form sold over the years, using 100 million US dollars (Source: Eli Lilly Annual Report, compiled by Harvest Venture Capital)

The patent for long-acting olanzapine injection expired in 2018, there is no generic drug so far, about 400 million to 500 million US dollars of varieties, as long as it can be made, no manufacturer will refuse, once again confirming the high
threshold of long-acting preparations.

Leuprolide microspheres for injection

Leuprolide is a synthetic heptepide analogue of naturally occurring gonadotropin-releasing hormone that has greater potency than natural hormones and is primarily used to treat breast, prostate, endometriosis and central precocious puberty
.
Initially available as a daily injection, leuprolide microspheres for injection (January/March preparation)
were developed.
Checking the FDA's annual Orange Book list, AbbVie's original LUPRON daily injection was withdrawn from the market
in 2011.

Leuprolide microspheres for injection have been sold for more than 30 years since they were approved by the U.
S.
FDA in 1989, and this product is developed and produced by Takeda, who is responsible for the commercialization of the Eurasian market and AbbVie is responsible for the commercialization
of the U.
S.
market.
Looking at the annual reports disclosed by AbbVie over the years, the sales data since 2012 are all leuprolide microspheres for injection, and its sales have remained at about $800 million in the past decade, and the decline in the past two years is due to the supply of raw materials
caused by the global epidemic.
In 2021, global sales of leuprolide microspheres for injection will be around
$1.
5 billion.

At the same time, the U.
S.
market contributes the vast majority of the drug's revenue, and its annual report also mentions the attribution of performance in those years with strong sales growth, attributable to the growth in demand and favorable prices
in the US market.
Only the manufacturing process threshold is high, eliminating the later imitators, so that it can maintain higher pricing and obtain more objective sales
for many years.

Regarding the difficulty of developing this variety (Data 6), in 2020, the FDA directly allocated $5 million for five years to the University of Michigan and the University of Maryland to establish a replica of
complex high-end formulations.
The news mentioned that some products after losing their patents, due to too complex to imitate, gave two typical examples, one is the injection of leuprolide microspheres, the other is the above-mentioned amphotericin B liposome (2021 has been the first imitation).

Back in China, CDE has frequently issued various guidelines in recent years to enable domestic companies to produce high-quality drugs
.
On June 28, 2020, the CDE publicly solicited opinions on the "Guidelines for the Design of GnRH Agonists for Advanced Prostate Cancer Clinical Trials", which contains requirements for generic drugs, the indicators mentioned can be PK or PD, and on November 26, 2020, the Notice of the Guidelines for the Design of GnRH Agonists for Clinical Trials of Advanced Prostate Cancer (No.
45 of 2020) was issued, which determined that only PK was required
for generic drugs 。 Under the control of CDE's high quality, some domestic enterprises that try to develop this variety of generic drugs with lower difficulty PD indicators
have been eliminated.

Figure 12 Liang propylene Ruilin has been selling over the years, using 100 million US dollars (Source: AbbVie Annual Report, compiled by Fengshuo Venture Capital)

Microspheres of triprelin for injection

Tripralin and leuprolide have a similar mechanism of action and are synthetic decapeptide analogues
.
First approved in France in 1986, there are currently January preparations, March preparations and semi-annual preparations, and the January formulation and March preparation of the original research IPsen DECAPEPTYL expired as early as 2010 (data 7), even so, sales in recent years have increased year after year (except for the impact of the epidemic in 2020), and sales in Europe and emerging markets alone reached 459.
6 million euros in 2021 (China accounted for 21% of the total).
That is, about 670 million yuan), the 2022Q1 quarter continued to maintain high growth, an increase of 21.
6%
year-on-year.
All this is due to the high threshold, low competition and good varieties, and there are still no generic drugs
of this variety 12 years after the expiration of the patent.

Figure 13 Quprelin sales over the years, 100 million euros (Source: IPSEN Annual Report, Compiled by Harvest Venture Capital)

4 Cannot be imitated

Irinotecan hydrochloride liposome injection

Irinotecan is a camptothecin analogue, as a prodrug, metabolized in vivo to the active metabolite SN-38, has become one
of the key drugs for metastatic CRC 。 Pfizer original research CAMPTOSAR irinotecan hydrochloride injection of the U.
S.
patent expired in 2008, generic drugs flocked to, the year's sales immediately from 969 million US dollars in 2007 will be 563 million US dollars in 2008, a drop of 41.
90%, the US market contributed more than half of the sales (data 8), as can be seen from the following figure, it means that as long as the threshold is low, generic drug manufacturers will not let go of about 400 million to 500 million varieties (the US market).

Figure 14 Irinotecan ordinary injection varieties approved by the FDA over the years (red represents delisting, source: FDA, compiled by Fengshuo Venture Capital)

Based on the rapid metabolism of irinotecan and some acute toxicity (gastrointestinal toxicity, etc.
) caused by systemic exposure, more clinical application value
of irinotecan is explored by using liposome wrapping to prolong its half-life and improve the systemic distribution of the drug.
The first irinotecan liposome injection ONIVYDE was approved by the US FDA in 2015 for the second-line treatment of metastatic pancreatic cancer, and sales have been relatively stable in recent years, achieving sales of 127.
4 million euros in the North American and European markets in 2021, and sales in 2022Q1 increased by 51.
4% year-on-year, achieving a large growth rate
.
At present, the indications are still being expanded, including lung cancer, stomach cancer and other solid tumors, and the incremental market is relatively broad, and some analysts predict that its sales peak will be $1.
5 billion (data 9
).

Figure 15 Irinotecan liposomes have been sold over the years, 100 million euros (Source: IPSEN Annual Report, compiled by Fengshuo Venture Capital)

According to the FDA Orange Book disclosure, ONIVYDE's U.
S.
patent expires in 2037 at the latest, while China's formulation patent expires in 2025 (there is no key composition patent), and the huge patent difference between China and the United States enables domestic capable drug manufacturers to imitate it in advance and enjoy the incremental market
where the original research is still expanding.

Paliperidone palmitate long-acting injection

Paliperidone is an atypical antipsychotic drug, is the main metabolic product of risperidone, the development path is similar, in 2006 the United States was approved as a daily oral preparation INVEGA, in 2009 the United States was approved as a January preparation INVEGA SUSTENNA, in 2015 the United States was approved as a March preparation INVEGA TRINZA, in 2021 the United States was approved as a half-year preparation INVEGA HAFYERA
.

As can be seen from the figure below, the manufacturing threshold of pariperidone sustained release tablets, once the patent expires, the generic drug manufacturers will not be ruthless, and 6 generic drug manufacturers
have appeared in just a few years.

Figure 16 FDA approved paliperidone sustained-release tablet varieties over the years (red represents delisting, source: FDA, Fengshuo Venture Capital)

The emergence of two generic drug manufacturers in 2015 caused sales of paliperidone tablets to fall by 45.
72%
from $573 million in 2015 to $311 million in 2016.

The sales of the palliperidone long-acting formulation below is enough to illustrate its huge market space, 2010-2014 is the January preparation, 2015-2020 is the January preparation + March preparation, 2021 is the January preparation + March preparation + June preparation
.
Sales in 2022Q1 increased by 8.
6% year-on-year, and sales of long-acting formulations have not yet reached a peak
.

Figure 17 Paliperidone has been sold over the years, using $100 million (Source: Johnson & Johnson Annual Report, compiled by Harvest Venture Capital)

In the face of such a huge variety, generic drug manufacturers will certainly not let go, TEVA products have been made in 2021, but the US9439906B2 patent on the drug delivery scheme will not expire until 2028, TEVA is fighting with Johnson & Johnson (data 10).

In China, the patent of the same family CN101932327A was rejected, CN105560176A has not been authorized, and the difference in patent examination between the two places allows domestic powerful enterprises to benefit the majority of patients
earlier.

Suspension for liposome injection of bupivacaine

Bupivacaine is an amide local anesthetic, and unlike traditional bupivacaine injections, which can only provide intraoperative anesthesia for less than 7 hours, the suspension for liposome injection of bupivacaine expands the application scenario and can be used for analgesia 72 hours after surgery, and the significant analgesic effect can reduce the use
of addictive opioids.

PACIRA's bupivacaine liposome injection suspension, EXPAREL, was approved by the U.
S.
FDA in 2011 and achieved sales of $507 million in 2021, with 2022Q1 sales up 13% year-on-year and still in a period of
rapid growth.
Before 2020 (inclusive), it is only the US market, and then it will be the European and American markets
.

Figure 18 EXPAREL sales over the years, $100 million (Source: PACIRA Annual Report, compiled by Harvest Venture Capital)

Also due to the difference in patent examination between China and the United States, there is a "relay" manufacturing process patent US11033495B1 in the United States, the expiration time of the United States is 2041, eVenus is fighting with PACIRA (data 11), while There is no such family patent in China, and all patents have expired
.

Aripiprazole long-acting injection

Aripiprazole is an atypical antipsychotic drug with a similar development path to antipsychotics, with ABILIFY as a daily oral tablet approved in the United States in 2002 and ABILIFY MAINTENA
approved in january in 2013.

As can be seen from the chart below, the daily preparation of paliperidone with a low manufacturing threshold, once the patent expires, the generic drug manufacturers, as usual, flood the entire market
in just a few years.

Figure 19 Fda approved aripiprazole daily preparation varieties over the years (red represents delisting, source: FDA, Fengshuo Venture Capital)

As can be seen from the sales situation in the chart below, in the face of white-hot competition among daily dosage form generic drug manufacturers, the sales of aripiprazole daily dosage forms fell from 654.
2 billion yen in 2014 to 347.
5 billion yen in 2015 and then to 95.
4 billion yen in 2016, a decrease of 46.
88% and 72.
55%,
respectively.

At this time, the apiperizole long-acting dosage form that has just been approved for listing has faced difficulties and maintained a positive sales growth rate for many years, with sales in 2021 at about 1 billion US dollars, a year-on-year growth rate of 12.
28%, and the market is mainly the United States, Japan and Europe
.

Figure 20 Aripiprazole sales over the years, 100 million yen (Source: OTSUKA Annual Report, compiled by Fengshuo Venture Capital)

Also due to the difference in patent examination between China and the United States, generic drug manufacturers in the United States cannot be successfully imitated, which has caused great trouble
to its listing and sales.
The key patents for compositions on the Chinese side expire in 2024, and similar in the United States, but the U.
S.
side also includes patents for specific populations that are similar to "indications" that expire in 2034, while China does not have this patent
.

This patent protects patients with aripiprazole for strong metabolism of the CYP2D6 or CYP3A4 enzymes and the simultaneous use of both enzyme inhibitors
.
Clinically, aripiprazole is generally combined with other CNS drugs, such as CYP3A4 inhibitor ketoconazole, CYP2D6 inhibitor quinidine, fluoxetine or paroxetine, which causes great trouble
to generic drug manufacturers in practical application.

The following figures are some summaries
of this article.

Figure 21 Summary of highly complex preparations (compiled by Harvest Venture Capital)

epilogue

At this point, the high threshold and perennial high profit margin properties of highly complex preparations have been elaborated very clearly
.
Today, the profit margin of some innovative drugs in China is no longer as good as that of some biosimilar drugs with relatively loose competitive space, if it is still blindly "labeling" investment, at least in the domestic pharmaceutical investment, it is inevitable to have a chicken feather
in the end.
Because of the gap between China and foreign countries that do not meet clinical needs, the main contradiction in the future for a long time is still to fill the gap in clinical needs, but the path taken is not the same, the famous, the story is beautiful and easy to raise funds, called "innovative drugs", high-end complex preparations with "imitation" labels have been subjected to the same treatment
as generic drugs of ordinary preparations.
It should be known that these high-end complex preparations of generic drugs, even abroad have a huge unmet clinical demand, and the current domestic "innovative drugs" can meet the unmet clinical needs of foreign countries?

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