Anti-AIDS drugs: opportunities that should not be missed

Medical Network June 26, 2018, the National Drug Administration approved a number of new anti-AIDS drugs listed, coupled with in-depth medical reform, China's AIDS treatment market is changing.

Drug development continues to break through

AIDS is a serious life-threatening disease. According to data released by the World Health Organization (WHO) in 2017, there were approximately 36.7 million people living with HIV (HIV) worldwide in 2016, with a total of 1 million fatal cases. Although the incidence of AIDS in China is low, data from the National Health and Wellness Commission show that by the end of 2018, the estimated number of HIV-infected people in China is about 1.25 million.

In the past 40 years, human beings have made great achievements in the control of AIDS. On the one hand, the protection measures have been continuously improved, and on the other hand, the research and development of anti-HIV drugs has continued to break through. Although AIDS vaccine research and development has not been successful, the latest cocktail therapy has made AIDS a controllable chronic disease. According to the National Institutes of Health (NIH), cocktail therapy has permanently suppressed the virus in nearly 50% of AIDS patients in the United States (blood viral load is less than 50 copies/ml, detection limit); the past 15 years, the United States AIDS deaths fell by 55%.

The first pharmaceutical companies in the United States to engage in AIDS research were Merck, Bristol-Myers Squibb (BMS) and GlaxoSmithKline (GSK), of which GSK took the lead with the Qidufu Ding of the company. In fact, zidovudine in the early 1960s has been synthesized, but its initial position is anti-tumor drug. In 1983, the researchers found that zidovudine has anti-HIV activity. In 1987, Zidovuddin was approved by the US FDA to be listed as the first anti-AIDS drug in history.

The early anti-AIDS drugs were mainly the first-generation nucleoside reverse transcriptase inhibitors. The curative effect was general and the adverse reactions were very large. Although it can prolong the survival of patients, AIDS is still regarded as a super cancer. In the mid-to-late 1990s, anti-AIDS drugs increased rapidly, and new mechanisms of anti-AIDS drugs, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, have emerged. Under such a background, Chinese scientist He Dayi proposed a cocktail therapy – a combination of three or more antiviral drugs to reduce the resistance of a single drug, to minimize the replication of the virus, and to Some or even all of the damaged immune function of the body is restored, thereby delaying the progression of the disease, prolonging the life of the patient, and improving the quality of life.

Based on He Dayi's cocktail theory, GSK launched the first combination therapy Combivir (lamivudine + zidovudine) in 1997. Clinical trial data showed that Combivir was combined with other antiviral drugs, and disease progression and mortality were reduced by half (9.6% vs 19.6%) compared to mainstream therapy at the time. Since the launch of Combivir, combination therapy has become the mainstream of AIDS treatment. In 2000, GSK launched the first three-way therapy Trizivir (lamivudine + zidovudine + abacavir); Aibowei launched the first combination therapy with protease inhibitor Kaletra (ritonavir) +Lopinavir), human control of AIDS has begun to make a qualitative leap. Despite this, the active ingredients of these compound products have the same mechanism of action, and the combination of antiviral drugs that require other mechanisms cannot be called “full-course cocktail therapy”.

The first full-course cocktail therapy was Gilead's Atripla launched in 2006. The program consists of a nucleoside reverse transcriptase inhibitor tenofovir, a non-nucleoside reverse transcriptase inhibitor, efavirenz, and an HIV reverse transcriptase inhibitor, emtricitabine. The advantage is that the virus inhibition rate is high. The adverse reactions are small, and it is the first one-day combination, and the convenience is very good. Since Atripla, convenience has become the third major consideration in the design of cocktails for the treatment of AIDS in addition to efficacy and adverse reactions. In 2012, Gilead added the integrase inhibitor Averyvir for the first time in the cocktail combination program. With the help of integrase inhibitors, the treatment regimen further strengthened the control of HIV and the drug resistance decreased significantly.

Under the control of numerous cocktail therapies, AIDS has become a controllable chronic disease. Even in the highly resistant patients, Ibalizumab, approved by the FDA in 2018, has the potential to suppress the resistance of most patients.

Who is the main ups and downs in the drug market?

GSK is the first company to introduce HIV treatments and is the first company to introduce HIV combination therapy. The company has seven related new molecular entities and is the ruler of the early HIV treatment market. Gilead is a rising star in the field, and its product tenofovir was approved by the FDA in 2001. Since then, Gilead has acquired Triangle Pharmaceuticals and obtained emtricitabine (FDA approved in 2003); in 2004, Gilead Based on tenofovir and emtricitabine, the first "half-program" cocktail Truvada was launched and began to compete with GSK. Since Truvada needed to be used in combination with efavirenz, the company obtained some of the commercial rights to efavirenz through authorization, and in 2006 launched the first daily full-course cocktail Atripla. Because Truvada+ efavirenz's clinical data is already very adequate, Atripla cited the clinical data of the former directly.

After Atripla's low-cost listing, it caused a serious impact on GSK. After 2006, Gilead focused on the AIDS drug research and development pipeline on integrase inhibitors. Although Merck has taken the lead in this field, ritilavir is too large in dosage and has a short half-life, which is not suitable for development once a day. The full-course cocktail, which created a "out of the box" opportunity for Avi Reeve. Although Averyev is not a daily one in the true sense, Gilead has solved the weakness of insufficient half-life by adding the hepatic enzyme inhibitor cholestasi. Based on Ivy Reeve and Kobesta, Gilead launched Stribild and Genvoya, and the lead has been further expanded. In addition, Gilead has developed two cocktails, Complera and Odefsey, through the commercial authorization of rivivirin, and gradually “hegemonic” the AIDS drug market.

Although GSK remained silent on the surface during the 10 years from 2004 to 2013, GSK acquired the commercialization rights of doneiravir from Yanyeyi Company through ViiV. Dobravir is a best-in-class of integrase inhibitors. Based on dotivide, GSK launched Triumeq, which quickly developed into a “blockbuster” drug after it went on the market, creating tremendous pressure on Gilead. In response, Gilead will improve the efficacy of tenofovir to propofolfive (with improved efficacy, a significant reduction in adverse effects, and reduced doses), and introduce a second-generation integrase inhibitor, Bictegravir, although Bictegravir does not. It must be better than dotilil, but with the help of propofol and fostazin, the adverse reactions are lower, and the volume of the new product is much smaller than the previous generations of Gilead.

In the past 10 years, the market size of the AIDS treatment has increased from 10 billion US dollars to 26 billion US dollars. Gilead and GSK are the main driving factors. In addition to Gilead and GSK, companies involved in the anti-AIDS drug market are Merck, Johnson & Johnson, Aberdeen and BMS, and other companies have been completely marginalized. In 2015, GSK announced the acquisition of BMS's AIDS treatment pipeline. Among the remaining companies, only Merck and Johnson have launched cocktail therapy in the past five years. Although Merck has its own integrase inhibitor, it is not suitable for the development of daily cocktail therapy, so Merck's market share is difficult to expand. Johnson & Johnson Cocktail Therapy

It was developed on the basis of the authorization of Gillette and its propofol, and the initiative is still in the hands of Gilead.

Looking at the development of the AIDS treatment market, the strong are stronger and the weak are weaker. It is predicted that the market share of Gilead and GSK will further increase, while the market share of Aibowei, Johnson & Johnson and Merck will further decline.

Opportunities and challenges of generic drugs

According to data released by the WHO, only 19.5 million of the world's 36.7 million HIV-infected people are taking antiretroviral drugs, and WHO's goal for the next 10 years is to let the remaining 17.2 million HIV-infected people take antiretroviral drugs, which will be terminated in 2030. AIDS epidemic. Based on this expectation, the anti-AIDS drug market is expected to grow slowly. EvaluatePharma predicts that the compound annual growth rate of the anti-AIDS drug market will be 3.1% in the next five years. By 2022, the total sales of branded drugs will reach 30 billion US dollars. According to IQVIA data, the global AIDS treatment market has reached 30 billion US dollars in 2017. If it grows at this rate, the market size in 2022 will reach 34 billion US dollars.

In the past few years, a large number of anti-AIDS drug patents have expired. In the next few years, some cocktail product patents will also expire, which creates huge opportunities for generic drugs. According to IQVIA data, abacavir + lamivudine generics were launched in 2015, with sales reaching $150 million in 2017. In addition, the price of AIDS generic drugs in the United States is generally high, and the profit margin is larger than that of generic drugs.

Although there are many opportunities, there are many challenges. Although a large number of anti-HIV new molecular entity patents have expired, the mainstream of the anti-AIDS drug market is a daily cocktail program. Cocktail treatments generally have patent protection for joint use, and the patent coverage period is relatively long. For example, Atripla, which was launched in 2006, will not expire until 2026. Moreover, while the old generation of cocktail therapy was delisted, the original research company slightly updated the formula to launch a new generation of more powerful cocktails, which made the generic drug have no competitive advantage, and the second could not buy the reference preparation if it was not copied in advance. .

Faced with this situation, the development strategy of the international generic drug giant is a combination of imitation and creation: based on the commonly used clinical programs, the new molecular entity with expired patents develops the cocktail program 505b2, because many treatments are commonly used in clinical practice. For Pre-Ind, you can apply for clinical relief from the FDA. The products include Mym's Cimduo, Symflo, and Symfi, Celltrion's Temixys. In addition, the method of changing the salt type of the compound and optimizing the proportion of the combination scheme can also bypass the patent protection of the original research drug, and the representative product has the lamivudine + zidovudine + nevirapine tablets of Hitero.

The biggest advantage of Chinese companies in developing anti-AIDS generic drugs is the possession of raw materials. China is the world's largest exporter of APIs, and AIDS drugs are difficult to synthesize, demand is small, and prices are high. It can control the competition of other generic drugs by controlling APIs. Therefore, for China's generic drug companies, AIDS drugs may be a good choice for going to sea.

The domestic AIDS treatment market is small, but there are many opportunities. In 2017, China's AIDS treatment market is only 1 billion yuan, with a low starting point and low competition. At present, there are about 1.25 million HIV-infected people in China, and the demand for treatment is huge. In the United States, the cost of antiretroviral treatment for HIV-infected patients is about 20,000 to 40,000 US dollars per year. Even if the cost of treatment in China is only 5% of the United States, the potential market capacity of anti-AIDS drugs in China is more than 12 billion yuan. At present, AIDS can be treated free of charge in China. Under this model, the AIDS drug market is not very active. However, with the economic development, the country is paying more and more attention to people's livelihood, and medical insurance is changing from “from scratch” to “from good to excellent”. AIDS drugs (including anti-AIDS drugs and AIDS opportunistic infections) are listed in 2018. The annual edition of the Essential Medicines List, the registration of new HIV drugs was included in the priority review, and the accessibility of Chinese anti-AIDS drugs quickly caught up with the international advanced level in just one or two years. In addition, the "China AIDS Treatment Guide (2018 Edition)" was released, which proposed the whole process of AIDS management, treating AIDS as a chronic disease. All the factors that are conducive to the market have been formed, and the change of the guarantee mechanism is expected to make the AIDS treatment market in China enter a virtuous circle.

Compared with the US market, China's AIDS treatment market has more opportunities. Because China's AIDS treatment market is very deserted, many original patents have not entered China, which is definitely good for Chinese generic drug companies , and the opportunities are those who are ahead of schedule.