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2018 new drug research and development red black list
The medical network on December 25th went to the end of the inventory period. From many perspectives, 2018 is an important year in the history of pharmaceuticals.
So far, the FDA has approved 55 new molecular drugs, breaking the record of 53 new drugs in the first year of the PDUFA system in 1996, much higher than the historical average.
The same record is the entry of capital. So far this year, there have been more than 300 IPOs/issuances in the health sector with a total financing value of over US$40 billion. Among them, 70 biotechnology IPOs and total financing of 8.2 billion US dollars, ALLO and MRNA have successively solved the record of 320 million yuan and 610 million US dollars.
The anti-tumor drugs with PD-1 as the core and the hypoglycemic drugs represented by GLP have ruined the refractory diseases, and the progress of many rare diseases and new drugs is exciting.
On the other hand, one will become famous and there will be countless failures after each successful new drug.
Red list
Record harvest year
The most prominent event of the year is undoubtedly the FDA's approval of a record number of NCE (New Chemical Entity, new compound).
Among them, highly innovative two types of future drugs that are in the market for decades are unusual in this year – the first gene therapy Luxturna, and the first RNAi drug is also the first hATTR nerve injury therapy Onpattro.
The FDA approved the first TRK inhibitor, Vitrakvi, based on pan-tissue drugs, and the EMA approved the first nanobody to be the first aTTP drug Cablivi.
In addition, Epidiolex from cannabis was successfully launched this year; the highly competitive three CGRP antibodies hit the line almost simultaneously, and migraine patients had preventive drugs.
In addition to the growing maturity of new drug development technologies, the precision of disease treatment, the popularity of target-centered discovery models, and the friendly attitude and high efficiency of the drug regulatory authorities are also the driving forces for the increase in the number of new drugs.
Star anticancer drugs, hypoglycemic drugs climb the peak again
The anti-cancer army led by PD-1 continues to regain lost ground.
The success of the tests such as KN042 and KN407 has enabled Keytruda to completely control the most important market for the first-line treatment of lung cancer. Although Roche's ABCP combination has also been approved, it is difficult to incite patients with high PD-L1 expression using a single K drug, low expression of new standard therapy using K drug plus chemotherapy.
Although Imfinzi successfully occupied Phase III lung cancer due to the PACIFIC test, Mystic combined with CLTA4 antibody completely failed in the fourth stage of lung cancer. The similar combination of Squibb also has a poor prospect. According to the positive results of the TMB stratification, it is not known whether it can be recognized by the drug supervision and payment department.
Tecentriq combined with chemotherapy in the first line to reduce the risk of death by 30%, and in the third-negative breast cancer (TNBC) as a first-line drug, it also significantly reduced the risk of progression and death, becoming the first new mechanism drug to prolong the lifespan of these two types of patients in more than 20 years. .
Pfizer and Merck's Bavencio/VEGF inhibitor Inlyta combined with the old standard therapy Sutent in the first-line clinical trial of first-line renal cancer, significantly prolonging PFS.
After a few decades of no drug abuse, AML has ushered in eight new drugs, including highly innovative drugs such as IDH inhibitors for tumor metabolism.
Another major disease progression is diabetes, weight loss drugs with GLP as the core. These drugs not only have hypoglycemic effects, but also have a significant weight loss effect, and are shown to reduce cardiovascular events. The dosage form can be administered once a week, and the oral dosage form is also expected to be listed in the near future. The compliance is not lost to the old drug. The strongest in the limelight is Novo Nordisk's Somarupeptide, which announced several PIONEER series Phase III clinical trials this year to beat similar and other major mechanisms of diabetes drugs. Lilly's GIP/GLP double agonist LY3298176 defeated its own GLP agonist, Turlicity, in both phase II clinical trials for hypoglycemic and weight loss.
Although diabetes has many drugs, its efficacy and compliance need to be improved. To encourage more capital to enter the world's largest chronic disease treatment field, the FDA is considering canceling the requirements for cardiovascular safety tests this year.
Multiple new mechanism drugs approaching the end point
The most surprising surprise is the Amarin fish oil formulation EPA. The drug was associated with a 25% lower cardiovascular event and a 20% lower risk of death in patients with well-controlled LDL but higher TG, showing statin-level efficacy, superior to SGLT2 inhibitors and GLP agonists.
In addition, the JAK1 inhibitor filgotinib reached all endpoints in a phase II clinical trial of rheumatoid arthritis. TYK2 inhibitor BMS-986165 Psoriasis phase II clinically achieved 75% of patients achieved PASI75 (75% remission). Phase III clinical trials of Pfizer's small-molecule ATTR drug tafamidis showed a 30% reduction in mortality compared with placebo, showing similar efficacy to RNA drugs. Novartis spent $2.1 billion to acquire Endocyte to acquire its small-molecule prostate cancer drug 177Lu-PSMA-617, and joined hands with the é•¥177 conjugate drug Lutathera to consolidate its dominance in the field of targeted radiotherapy.
Confirmation of the mechanism drug "rejuvenation"
Novartis's PI3K inhibitor alpelisib combined with fulvestrant in the PIK3CA variant, HR-positive, HER2-negative advanced breast cancer patients reduced the risk of progression by 35% compared with fulvestix alone, becoming the first PI3K inhibitor to show solid tumor activity .
Clovis's PARP inhibitor Rubraca produces a 44% response rate in the second-line prostate cancer test of TRITON2, which is expected to expand the range of use of PARP inhibitors.
The combination of “O medicine + Y medicine†showed a higher response rate before surgery in patients with stage III disease, and IO entered the forefront of tumor treatment.
Multiple drugs from drugs are listed or show market potential. The FDA approved the cannabinol (CBD) liquid formulation Epidiolex for the treatment of two rare epilepsy Lennox-Gastaut and Dravet syndrome. Yangsen Pharmaceutical's D-Ketamine nasal administration has reached the end point in two phase III clinical trials and is expected to be available soon. Zogenix's low-dose fluoroamphetamine formulation ZX008 reduced the number of sputum cycles by 54.7% per month in the second phase of Dravet's syndrome phase III, reaching the test primary endpoint. The psychedelic mushroom active ingredient, celacetibine, begins clinically in antidepressant phase II.
In addition, the combination of the central scorpion muscarinic receptor M1/M4 double agonist xanomeline+ peripheral choline receptor antagonist tresine chloride began clinically in AD and schizophrenia phase II. The high taurine prodrug ALZ-801 will begin the ADII phase. Injection of capsaicin preparation CNTX-4975 began two phase III clinical trials of osteoarthritis.
New technology on the road
Early clinical trials of Sarepta's DMD gene therapy resulted in 38% of normal muscle nutrient levels.
The design of CAR-T is more and more complicated. Various types of brake devices, multi-symbiosis signals, multi-antigen recognition and other designs (such as 1928z-41BBL, 4SCAR2.0, etc.) have expanded the treatment window and are expected to solve the problem of drug resistance.
MicroED technology resolves the high resolution chemical structure of very small sample mixtures in minutes.
In addition, apparent transcriptomics (epitranscriptomics, chemical modification of regulatory RNA), light-sensitive ADCs, single-base repair gene editing, and induced protein degradation techniques such as PROTAC and interference protein stability techniques have all received strong early capital support.
Product/ technology flow is smooth
There are not many large acquisitions this year, but they are still relatively healthy.
Takeda's $62 billion acquisition of Shah is the biggest acquisition, Sanofi's $11.6 billion acquisition of hemophilia manufacturer Bioverativ, and the new base of $9 billion to acquire CAR-T drug manufacturer Juno.
Glaxo's 5.1 billion acquisition of Tesaro (TSRO) was questioned by investors, losing nearly three TSROs that day.
Sanofi's $4.8 billion acquisition of Belgian biotechnology company Ablynx, the first Nanobody drug Cablivi.
BI acquired Viratherapeutics, an oncolytic virus development company with preclinical assets for $244 million, and acquired OSE's preclinical SIRP-alpha (CD47 receptor) antibody OSE-172 for a down payment of $37 million and a total value of $1.35 billion.
Merck has acquired the oncolytic virus manufacturer Viralytics for $394 million.
Cooperative development that complements each other is becoming more and more mainstream.
Pfizer and Novartis jointly developed NASH combination therapy, and invested $120 million in down payment and $305 million in miles to develop BioNTech's mRNA flu vaccine.
Johnson & Johnson and RNA drug company Arrowhead reached a total of 3.7 billion US dollars in cooperation.
SQZ Biotech will collaborate with Roche for a total of $1 billion to develop new APC cell therapies using its physical delivery technology.
Baijian hired antisense nucleic acid company Ionis for a neurological medicine for a total value of $1 billion.
Kite core member A round of financing of $300 million set up Allogene, taking over Pfizer and Cellectis to develop a product line for allogeneic CAR-T, including the already clinical UCART19, UCART123 and 16 other preclinical targets.
Asrekone received the NKG2A antibody monalizumab from Innate Pharma SA for a down payment of $100 million.
Black list
IO also has many losers
The development of new immunotherapy drugs after PD-1 is not satisfactory.
The biggest failure this year was when the IDO inhibitor epacadostat/K drug combination ECH-O301/KN252 was terminated early due to ineffectiveness. Later, Incyte announced the late stages of epacadostat and Merck, Squibb, and AstraZene PD-1/PD-L1 drugs. Clinical trials will stop recruiting patients. Bristol-Myers Squibb also discontinued several clinical trials of PD-1 combined with their IDO inhibitor BMS-986205, which was acquired from Flexus for $1.25 billion.
In addition, there was almost no single-way response in the early clinical trials of STING agonists and TIGIT antibodies; the Lag3 antibody of Merck also had a 6% response rate. Previously published data on targets such as 4-1BB, GITR, CSF1R, A2AR, and OX40 failed to meet expectations.
Disappointed "cytokine year"
The year 2018 was called the year of cytokines, but the data for the second half of the year was disappointing.
Squibb obtained a 35% interest in Nektar's IL2 derivative NKTR214 with a $1 billion down payment, $850 million in equity, and a total value of $6.33 billion. However, the two batches of data released later were far less than the early data of last year.
Eli Lilly's $1.6 billion in cash acquisition of Argo BioSciences' Peg-IL10 formulation pegilodecakin was not as effective as expected.
The ON12 IL12 formulation also produced a 22% response in combination with PD-1.
Slow disease drugs hit one after another
In the AD field, Lilly and Asrekone terminated their BACE inhibitor lanabecestat. vTv's RAGE receptor antagonist Azeliragon is a clinically unworthy placebo in a phase III trial. Bai Jian and Eisai's BAN2401 Phase II clinical trial Study201 announced that it had reached the end point, but later found that the group was severely uneven, basically a failure test.
In terms of analgesics, the 100-key Nav1.7 ion channel blocker vixotrigine failed to reach the end point in a Phase II clinical trial of sciatica, which would terminate the development of this product in this indication, and Roche also terminated the development of similar products. The greatest hope for painkillers, Tanezumab, achieved a lower improvement than placebo, although both phases reached all endpoints. The regenerative drug of the same type of antibiotics stopped the high-dose group because of the deterioration of OA. Several similar drugs have previously withdrawn from the field because the treatment window is too small or difficult to determine. Trevena's injection of morphine analogues, the preferred opioid receptor agonist oliceridine, was shot down by the FDA panel of experts with 7 votes in favor and 8 votes against.
In addition, ALKS's two combination of drugs have been hit hard in antidepressant and anti-sperm. Ironwood will return the gout drug to Lesinurad and its fixed dose combination with allopurinol, Duzallo, to AstraK. Novartis terminated the early development of antibiotics and antiviral drugs. Dietetic company Orexigen filed for bankruptcy protection.
Orphan drug encounters several roadblocks
One of Akcea's flagship products, the familial chylomicronemia (FCS) drug, Waylivra, was rejected for induction of unpredictable severe thrombocytopenia.
The first in vivo gene editing therapy, Sangamo's Hunter's disease in vivo gene editing therapy SB-913, failed to detect the enzyme (IDS) expressed in the peripheral blood of patients in early trials.
Pfizer's DMD drug, a phase II clinical trial of the myostatin antibody domagrozumab, failed to reach its end and was discontinued.
Some patients with hemophilia gene therapy SPK8011 produced an immune response that reduced FVIII factor levels to less than 5%, and the remaining patients had an average FVIII factor of 30% of normal.
Bellicum's T cell therapy BPX-501 caused 3 brain damage in clinical trials, and all US clinical trials were stopped.
Summary<<<
In 2018, the hard-won achievements were accompanied by a downward trend in the return on investment in new drugs. Although the number of new drugs is record-breaking, most of them are new drugs with small disease types, the central nervous system with the most disease burden, the treatment of degenerative diseases and solid tumors, and still lack of subversive new mechanism drugs.
The massive entry of capital into biopharmaceuticals is generally good for the industry, but it also encourages risky behavior. These advances are at the expense of high costs and market fragmentation, while marginal diminishing effects do not allow for unrestricted risk. Some mechanisms have limited mining value, and areas with mining value have attracted too many competitors.
In order to protect the high enthusiasm of investors, the industry needs to deepen the understanding of the fundamental principles of new drugs, with science as the core competitiveness, and avoid frivolous gambling research and development activities. Luck can't be a core competency. Sustainable development relies on every detail and deep scientific support for each step. The industry needs to be awesome about the complexity of biological processes. (The author of this article is from the source of US medicine)