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Viagra

From the failure of cardiovascular medications to the great success of ED indications

In the 1980s, scientists at Pfizer’s European Research Center have been looking for drugs to treat cardiovascular diseases such as angina. The commonly used nitrates at that time were prone to tolerance. At that time, basic research had found that phosphodiesterase (PDE) was the main link in degrading cyclic nucleotides, while the PDE family contained multiple members, among which PDE5 could degrade cGMP. And concentrated in vascular smooth muscle and platelets. The experiment found that selective inhibition of PDE5 can simultaneously play a role in vasodilation and anti-platelet aggregation.

In 1986, Pfizer set up a special research team to carry out the work of PDE5. At that time, the known PDE5 inhibitor Zaprostol activity and selectivity were not high. On the basis of Zapulast, the scientists synthesized a series of 2-alkanes. The oxophenyl substituted heterocyclic compounds, and a series of modification and modification of the methyl, ethoxy, and the substituents of the compounds, obtained 13 new compounds:

Considering factors such as in vivo activity, solubility, and enzyme inhibition levels, Pfizer eventually chose compound 10, number UK-92480, to enter the next step, which was the later famous sildenafil. In 1989, sildenafil entered preclinical studies in the form of its citrate, and in 1991 it began to treat clinical trials of hypertension and angina. Early clinical data showed that sildenafil does have certain vasodilatory effects and can moderately lower blood pressure, but due to its short half-life, it is difficult to obtain sustained antihypertensive effects. There are significant defects in both pharmacodynamics and pharmacokinetics.

In clinical studies, sildenafil occasionally found side effects that increased the frequency or duration of penile erection, but this phenomenon only occurred in subjects who received multiple consecutive doses, and could not confirm whether it was in the middle-aged and elderly patient population. effective. In 1990, Louis Ignarro (received the Nobel Prize in Medicine in 1998) confirmed that NO (nitric oxide) is an important signal molecule involved in penile erection, and Pfizer scientists found that in the state of sexual excitement, the penis nerve The vascular endothelium releases NO, which then diffuses into the cavernosal smooth muscle cells, and induces increased intracellular cGMP levels. Sildenafil inhibits PDE5, slows down the rate of cGMP degradation, and increases congestion and prolongs erection time.

In order to evaluate the efficacy of sildenafil more rigorously, clinical studies need to address a number of issues, such as whether large-scale clinical studies are effective, whether recruiting patients need to set a specific ED patient, and whether long-term use of drugs will produce tolerability. The most critical question is how to assess the efficacy of sildenafil?

This can not be accurately assessed by drawing blood samples. After all, it involves patient personal privacy and evaluation of objectivity issues. Despite the difficulties at the time, the researchers took a self-evaluation of the subjects and their partners for clinical studies. The researchers carefully designed a set of questionnaires and records, of which the most representative were the International Erectile Function Index (IIEF) and other questionnaires. Under this design, clinical studies including clinching 514 male patients were conducted in 32 clinical centers. The results of the study showed that Sildenafil has therapeutic effects on ED caused by different causes, followed by several large clinical trials. Studies have confirmed this good effect.

In 1998, the FDA and EMEA approved the Sildenafil Citrate Tablet, which is known as Viagra (commonly known as Viagra). Since then, the story must have become a household name. Viagra became the best-selling global blockbuster drug (with a peak sales value of approximately US$3 billion), which brought Pfizer a large-capacity printing press. As of this writing, the story of sildenafil has not yet ended. In the large SUPER-1 clinical trial launched by Pfizer in 2002, sildenafil showed a good effect in treating pulmonary hypertension. In 2005, the FDA and the EMEA approved sildenafil for the treatment of the indications of PAH marketed under the brand name Revatio (Ruifeide). In 2010, it was approved for a new intravenous fluid formulation. Despite the current indication (another indication that the drug Bosentan was included in this year’s Medicare negotiations but not successful), the sales volume is modest (it should have a certain relationship with the indication patient base), but Sildenafil has experienced a Fan Xuan, first failed clinical studies of cardiovascular and blood pressure reduction, and then to the accidental discovery of the treatment of ED side effects, and then to obtain large commercial success after mass market approval, and finally in the pulmonary hypertension (this indication has not yet been approved in the country, Do not know if there will be off-label) areas to regain opportunities.

We can think from it that the discovery process of innovative drugs is both scientific and artistic, and there are many contingencies under a very low probability of success. These contingencies need to be confirmed through systematic research, including forward-looking basic research and scientific rigorous clinical research. The design, efficient and solid compound modification and screening, and perseverance in research are all indispensable.

GLP-1

Somaru peptide injection, what millions died that Caesar might be great!

Recently, Novo Nordisk’s new generation of GLP-1 drugs called Somaru peptides can be described as a friend circle, this dedicated and great pharmaceutical company author had previously in the May 10 essay “Novo Nordisk Did you invest in Shanhaiguan? As discussed in the article, we will not repeat them here. In the 2016 annual report of the company, we can see the field of diabetes and weight loss indications. The main varieties of the company’s layout are somarubin injections. The code is NN9535:

Of course, Somaru peptides are not only an internal code for NN9535, but also NN9536 for weight loss, NN9931 for NASH (non-alcoholic steatohepatitis), and long-acting hypoglycemic agent NN9924 for oral administration. From the numbering, it can be seen that Novo Nordisk reserved more than one long-acting GLP-1 drug in the early stage, and that Somaruil is the best drug candidate left after thousands of choices. From “Discontinued drug therapies to treat diabetes in 2015” we can see that just in 2015, Novo Nordisk stopped NN9926 (oral), NN9927 (oral), and NN9928 (clinical trial registration information shows that 9928 is somarubil The author has not yet confirmed any difference with 9924. Welcome to correct the research and development of the three GLP-1 drugs, both for reasons of effectiveness and for strategic reasons (turn to more advantageous compounds).

With the failure of drug companies such as Eli Lilly and Merck in the GLP-1 drug field, GLP-1 drugs have lost six in 2015. If we add drugs that failed in 2014 and 2016, GLP-1 It can already be said that the bones are exhausted. After all, seven drugs were listed on the market. In fact, the core competition of GLP-1 drugs lies in the frequency of administration, hypoglycemic effect, weight and cardiovascular benefits, and immunogenicity. Such Novo Nordisk’s unique fatty acid chain modification technology still has such high R&D. The failure rate, many times the low success rate natural for innovative drug development is inevitable.

Opdivo

The first-line single-agent treatment of advanced NSCLC regrettably lost

On August 5, 2016, Bristol-Myers Squibb announced that the large phase III clinical trial of its PD-1 heavy drug Nivolumab (Opdivo) for the treatment of advanced NSCLC (PD-L1 TPS ≥ 5%) failed to reach CheckMate-026 Significantly improve the primary endpoint of progression-free survival (PFS).

The clinical study enrolled 541 patients, of which 271 received Nivolumab at 3 mg/kg (every two weeks) and 270 received platinum-based chemotherapy plus pemetrexed/gemcitabine/paclitaxel. The results showed that the primary endpoint of significant improvement in PFS was not achieved. After the announcement of the results, the stock price of BMS plunged 16% on that day and then went down. In the essay of November 25, the essay “Reflections on New Wealth Nights: Pharmaceutical Stocks in 2018, Big or Big Pets” mentioned that many domestic investors have not really received the risk education for innovative drugs. PD-1 A super heavyweight innovative drug is one of the best examples.

Several happy couples, some people are enjoying the stock price increase when the BMS stock price plummeted. On June 16, 2016, MSD announced that its Keytruda single-line treatment of PD-L1 with high expression (TPS ≥ 50%) of KEYNOTE-024 in advanced NSCLC Phase III clinical study reaches the end of the target in advance:

In October 2016, the US FDA formally approved KEYTRUDA as the first-line NSCLC treatment program for non-small cell lung cancer, adapted to patients with non-small cell lung cancer with high expression of PD-L1 (TPS ≥ 50%), no EGFR or ALK mutations. In the battle for first-line NSCLC, the BMS was left behind by Merck. The original PD-L1 level test that restricted Merck’s prescription in the second-line treatment helped them complete the first-line indication application sooner.

In fact, in CheckMate-012, when using nivolumab as a single agent (q2w), there are significant differences in objective response rate/year-to-year overall survival index, such as PD-L1≥50%, at different levels of PD-L1 expression. ORR data for patients with ≥1% and <1 were 50%, 28%, and 12%, respectively, and overall one-year survival rates were 83%, 79%, and 69%, respectively. Therefore, for BMS patients with TPS ≥ 5%, the criteria for enrollment can only be said to be unsatisfactory.

PD-L1 + CTLA-4

Uncertainty in the development of checkpoint inhibitors

On July 27, 2017, AstraZeneca announced the use of its combination PD-L1 monoclonal antibody durvalumab and CTLA-4 monoclonal antibody tremelimumab for first-line treatment of locally advanced or metastatic, EGFR and ALK wild-type non-small cell lung cancer. MYSTIC failed to reach the primary clinical endpoint of PFS. The stock price of AZ fell by nearly 14.91% on the same day, evaporated more than $6 billion in market value, and even the BMS with combined medications of Opdivo and Yervoy fell by more than three points.

AstraZeneca actually has not found anything in the field of oncology recently. Teresa has been very successful in the Chinese market. Fulvestrant has entered the negotiating list. However, the field of immunotherapy has always been the pain point of AZ. Originally it was PD- L1+CTLA-4 has high hopes. Now that PFS has not been reached, it is still unclear whether OS data can be disclosed next year. Of course, there is BMS in the effort to challenge immunocombination therapy. The combination of ipilimumab and nivolumab is still worth the wait.

CETP inhibitors

The four giants stepped forward

Atherosclerosis is prone to occur in the large and middle arteries, which can cause ischemia and anoxia in the blood supply tissue, coronary heart disease, myocardial infarction and other symptoms. Abnormal cholesterol levels are the main factors that trigger atherosclerosis. Three cholesterol-transporting lipoproteins can be divided into VLDL, LDL, and HDL according to their density. Basic research shows that inhibition of CETP activity can increase plasma HDLc levels, help reduce blood cholesterol levels, and reduce the risk of atherosclerosis. Therefore, the development of CETP inhibitors has become a contestable place for major pharmaceutical companies.

The torcetrapib, dalcetrapib, anacetrapib, and evacetrapib in the above figure are the structural formulas of the CETP inhibitor compounds developed by Pfizer, Roche, Merck, and Eli Lilly. After a long period of preclinical and clinical studies, Pfizer first announced in the ILLUMINATE study in 2006 that combined treatment with torcetrapib and astatafil increased mortality by 61% and other cardiovascular events. Follow-up studies have shown that not only can they not Reducing the risk of atherosclerosis may even increase the thickness of the intima-media of the blood vessel, a result that the previously invested $800 million in R&D costs did not translate into the output of the marketed drug. This is also one of the major failures in the history of Pfizer’s cardiovascular research and development.

In the follow-up, Roche, Merck, Eliard launched a large-scale clinical study on its own CETP inhibitors, and the number of patients enrolled in the study was tens of thousands. Among them, Roche was the first to stop and also suffered the least loss. In 2012, Roche stopped the Dal-OUTCOMES clinical study first. Lilly announced in 2015 that it stopped further research on evacetrapib. ACCELERATE Phase III did not find it adequate in patients with coronary heart disease. Effectiveness.

The MSD, which was the only data to be considered, also announced the results of the phase 3 clinical trial of REVEAL in 2017. Among the more than 30,000 subjects, cardiovascular disease death was caused by a 104% increase in HDL and an 18% decrease in LDL. The absolute risk of composite endpoint events consisting of myocardial infarction, myocardial infarction, and coronary recanalization was only reduced by 1% and relative risk was reduced by 9%. On October 12th, Merck announced that it would abandon the listing application for this drug. The CET inhibitor left only TA-8995, which the company had spent a lot of money betting on. The Big Four could be said to be thundering.

Afterwards, what are the causes of the tragic failure of CETP inhibitor drugs? Perhaps the mechanism of action of the HDL hypothesis is not established, perhaps due to off-target effects caused by molecular defects. Perhaps the type of effect of CETP on HDL has not been explored clearly. Perhaps the epidemiological correlation data may have misled the research direction, perhaps other The reason why the Big Four did not succeed in the market after advancing the expensive large phase III clinical trials has become a topic for further study.

The author firmly believes that the industry trends of innovative drugs do not look back. This will be one of the core long-term core lines of A-share investment in the future. We only need to be more rational, more patient, and more calm in the face of a vast market space. . After all, even if it is such an innovative leader in Hengrui Medicine, there are also non-allocatine, Umi Deji’s initiative to give up.

Every innovative pharmaceutical company needs to carefully balance market and risk, competition and time, input and output, especially in large areas such as cancer, diabetes, cardiovascular and cerebrovascular, CNS, anti-infection, and autoimmunity. In order to present the complex situation of group operations, multi-line and multi-target layout, single-drug + combined drug use, and own R&D + external cooperation, it can be said that the challenge faced by R&D personnel of drug companies is like managing fund managers. It is necessary to make a balanced allocation in multiple sub-fields, allocate R&D funds and resources, and make appropriate forward-looking layouts on multiple targets. It is neither too early (premature layout is more risky for domestic companies) nor too late ( Too late to have no first-mover advantage), and investment in the “half step earlier than the market” has the same purpose.

At the same time, just as funds need to consider the rate of return, R&D efficiency is also critical for huge R&D investment. Therefore, innovative drug development is like the long-term investment of large funds. One or two varieties cannot fully explain the problem. Multi-target, multi-field, multi-level, multi-dimension layouts are king for large companies, and do not outperform the market for one year. Difficult, difficult is ten or twenty years outperforming the market, why this year the market has given rise to such a big premium rate, perhaps this is also one of the reasons, just like the market has been repeatedly tested, has repeatedly proved their own funds The manager has the best chance to continue to win the market.

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