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In the first half of 2018, the FDA approved 20 new molecular entities and new biological products, including 15 new molecular entities and 5 new biological products.

1. Lutathera (lutetium Lu 177 dotatate)

On January 26th, the FDA approved Nutra Subsidiary France Advanced Accelerator Applications (Advanced Accelerator Application) Lutathera for the treatment of Gastrointestinal Pancreatic Neuroendocrine Tumors (GEP-NETs). This is the first time that radiopharmaceuticals have been approved by the FDA for the treatment of GEP. -NETs.

Lutathera structure

Lutathera, a Lu-177-labeled somatostatin analog, is an emerging peptide receptor radionuclide therapy (PRRT) that works by binding to a cell called somatostatin receptor. Suppressor receptors may exist on some tumors. After binding to the receptor, the drug enters the cell and releases radiation to damage the tumor cells.

Gastrointestinal pancreatic neuroendocrine tumors are a group of tumors that originate in the neuroectodermal layer and contain neuroendocrine particles. It can be found in different parts of the pancreas and the gastrointestinal tract, such as the stomach, intestines, colon, and rectum. It is estimated that about 27,000 people each year are diagnosed with gastrointestinal pancreatic neuroendocrine tumors.

Lutathera’s approval was supported by two studies. The first was data from a key randomized Phase III clinical study, NETTER-1, involving 229 patients with certain advanced somatostatin receptor-positive GEP-NET. Patients in the trial were enrolled in non-surgically cured midgut neuroendocrine tumours treated with Sandosatin, a drug that was marketed by Novartis, and compared Lutathera with double-dose Sandosatin. The data shows that Lutathera significantly reduced the risk of disease progression or death by 79%.

The second study was based on data from 1214 patients with somatostatin receptor-positive tumors, including GEP-NETS. The results showed that 16% of the 360 ​​GEP-NETs patients injected with Lutathera had partial tumor shrinkage.

2. Biktarvy

Biktarvy is a three-in-one combination formulation consisting of HIV-1 integrase chain transfer inhibitor (INSTI) bictegravir (50 mg) and two HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs) emtricitabine (200 mg) and Composition of tenofovir alafenamide (25 mg).

Bictegravir sodium salt structure

The Biktarvy indication is a complete protocol for the treatment of HIV-1 infection in adults without a history of antiretroviral therapy, or less than 3 months after receiving antiretroviral therapy and replacing antiretroviral therapy virology Inhibition (HIV-1 RNA load below 50 copies/mL), no history of failed treatments, and no previous response associated with resistance to individual components of Biktarvy.

The main safety assessment of Biktarvy was based on 48 weeks of data from two randomized, double-blind, active controlled trials (Trial 1489 and Trial 1490), recruiting 1274 HIV-1-infected, adult subjects with no history of antiretroviral therapy Of these, 634 subjects received one Biktarvy once a day.

In trials 1489 and 1490, at least 5% of subjects in the Biktarvy group reported the most common adverse events (all grades) as diarrhea, nausea, and headache. Treatment with Biktarvy, abacavir [ABC] / dolutegravir [DTG] / lamivudine [3TC], or DTG + FTC / TAF was discontinued. The proportion of subjects with serious adverse events was 1%, 1%, and <1%.

The additional safety of BIKTARVY resulted in 48 weeks of data based on 282 virologically suppressed subjects. In this randomized, double-blind, active controlled trial (trial 1844), the virus inhibits subjects from DTG + ABC/3TC or (ATV) (cobicistat or ritonavir) or darunavir regimens where virologic inhibition is affected. Participants converted from an atazanavir (ATV)-containing regimen to an open-label, 48-week data from an active versus a control trial for week 48 data DRV (administered with cobicistat or ritonavir) plus FTC/TDF or ABC/ 3TC to BIKTARVY (trial 1878) for comparison. In general, the safety of adult subjects with viral suppression in the 1844 and 1878 trials was similar to that of subjects without a history of antiretroviral therapy.

3. Symdeko (tezacaftor+ ivacaftor)

Cystic fibrosis is a rare genetic disease that shortens longevity, affecting approximately 75,000 patients in North America, Europe, and Australia, caused by defects or deletions in the CFTR protein caused by genetic mutations. Children must inherit two defective CFTR genes from their parents to develop cystic fibrosis.

Symdeko is used to treat cystic fibrosis patients 12 years of age or older. It is a combination of tezacaftor and ivacaftor, and it is also the third FDA-approved treatment for the underlying cause of cystic fibrosis.

Tezacaftor structure

Symdeko was approved mainly based on two phase III studies named EVOLVE and EXPAND. The study recruited a total of approximately 750 cystic fibrosis patients aged 12 years and older who carried two F508del mutations or carried one F508del mutation and mutation with residual CFTR function. In both studies, there was a statistically significant and clinically significant improvement in lung function and other parameters in patients treated with SYMDEKO and demonstrated safety.

4. Erleada(apalutamide)

Erleada (apalutamide) belongs to the second generation of highly selective androgen receptor (AR) antagonists, and its affinity for the androgen receptor is more than 5 times that of the first generation of AR antagonists. In August 2013, Johnson & Johnson acquired Argon Inc.’s ARN-509 (JNJ-56021927, apalutamide) for US$1 billion (US$650 million down payment and US$350 million in miles) as a supplement to its prostate cancer product line.

Apalutamide structure

The safety and efficacy of apalutamide was confirmed in a randomized study involving 1207 non-metastatic castration-resistant prostate cancers. Patients were randomized to apalutamide or placebo and received endocrine therapy, including gonadotropin-releasing hormone (GnRH) analogues, or surgical castration (removal of bilateral testes) to lower androgen levels in the body. The results showed that metastasis-free survival was significantly longer in the apalutamide-treated group than in the placebo group (40.5 vs 16.2 months).

Erleada has received FDA’s priority review status and is the first FDA-approved drug to treat non-metastatic castration-resistant prostate cancer. It is also the first drug to be listed on the clinical endpoint of metastasis-free survival (MFS). New tumor drugs. The so-called metastasis-free survival refers to the time from the beginning of treatment of non-metastatic tumor patients to the transfer of tumor cells to other organs of the body or death.

Prostate cancer is an androgen-dependent tumor. Androgens stimulate prostate cancer cell growth and disease progression. The treatment options for prostate cancer are relatively limited. Currently, the world’s best-selling prostate cancer drugs are Zytiga (Abiraterone, CYP17A1 inhibitor), Xtandi (Enzalutamide, androgen receptor antagonist). The former had global sales of 2.5 billion U.S. dollars in 2017, and the latter attracted Pfizer to purchase Medivation at a huge cost of 14 billion U.S. dollars.

5. Trogarzo (ibalizumab-uiyk)

Trogarzo (ibalizumab-uiyk) is an intravenously infused humanized immunoglobulin G4 monoclonal antibody that binds to a second extracellular domain of the CD4+ T cell receptor, preventing the HIV virus from invading these cells, and PRO140 Similar are all “virus intrusion inhibitors.” It is the first antiretroviral therapy with a new mechanism of action in more than a decade, and it is also the first sterile biologic manufactured in China and approved by the US FDA to enter the US clinical trial.

Trogarzo is a brand new antiretroviral treatment for adults who are HIV-infected and unable to respond to many existing therapies. The use of the method is that the patient is intravenously injected once every 14 days and can also be used in combination with other similar drugs.

Trogarzo’s safety and efficacy have been validated in a clinical trial. The trial recruited 40 patients with multidrug-resistant HIV who were severely treated and some had even received 10 or more antiretroviral treatments. However, the researchers found that even if the patients received a lot of treatment, the level of virus in their blood (HIV-RNA) was still high. However, in the original therapy, after one week of treatment with Trogarzo, most patients had a significant drop in HIV-RNA levels in their blood. After 24 weeks, HIV-RNA levels were suppressed in 43% of patients.

 6. Ilumya (tildrakizumab)

Psoriasis is a non-infectious chronic immune disease that occurs on the skin. It accelerates the growth cycle of skin cells and causes thick areas of the skin to appear. The most common form of psoriasis is plaque-type psoriasis, affecting approximately 80% to 90% of patients with psoriasis.

Ilumya (tildrakizumab) selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor, thereby inhibiting the release of pro-inflammatory cytokines and chemokines. At the completion of the 0 and 4 weeks of the initial dose, Ilumya was administered at a dose of 100 mg every 12 weeks by subcutaneous injection. Ilumya is not suitable for patients who are severely allergic to tildrakizumab.

The FDA approved data support based on the key phase III clinical project reSURFACE. In two multicenter, randomized, double-blind, placebo-controlled trials (reSURFACE 1 and reSURFACE 2), 926 adult patients were treated with ILUMYA (N=616) or placebo (N=310). Both of these studies met the primary efficacy endpoint and demonstrated significant clinical improvement with the administration of Ilumya 100 mg compared to placebo.

Of these, 74% (229) of the patients in the reSURFACE1 study achieved 75% skin clearance at 28 weeks after 3 doses, 84% of patients who continued to use ILUMYA 100 mg were able to maintain PASI 75 at week 64, and were re-randomly assigned. Only 22% of patients using placebo maintained this effect. Of the patients who received ILUMYA 100 mg and whose PGA score was “cleared” or “minimum” at week 28, 69% were able to maintain this response at week 64 and were re-randomized to receive placebo. Only 14% of patients can maintain this response.

7. Tavalisse (fostamatinib)

Tavalisse (fostamatinib disodium hexahydrate) is an oral spleen tyrosine kinase (SYK) inhibitor that responds to potential autoimmune causes of the disease by preventing platelet destruction and provides an important new therapeutic option for adult patients with chronic ITP. .

Fostamatinib structure

Chronic ITP is a rare autoimmune disease in which the immune system destroys platelets, which is necessary for normal blood clotting. This disease is difficult to treat because it is impossible to predict how people respond to available treatments. Tavalisse is used to treat thrombocytopenia in previously untreated adult patients with chronic immune thrombocytopenia (ITP).

Tavalisse’s approval relied on data from the FIT clinical study program, which included two randomized placebo-controlled Phase III clinical studies 047 and 048, an opening extension trial 049, and an initial proof-of-concept trial. The new drug market application included data on 163 patients with ITP and was supported by a safety dataset that included more than 4,600 subjects who had already received the TAVALISSE assessment involving other indications.

8. Crysvita (burosumab-twza)

X-linked hypophosphatemic rickets (XLH) is a rare hereditary disease and the most common hypophosphatemic rickets, affecting one in every 20,000 people. XLH is carried on the X chromosome. Although almost all X-linked diseases are recessive, XLH is one of the few dominantly inherited diseases.

On April 18, the FDA approved the listing of the monoclonal antibody drug Crysvita (burosumab-twza) for the treatment of XLH in children and adults 1 year of age and older. Burosumab, developed by the Japanese Pharmaceutical Association and Kyowa Kirin and Ultragenyx, is a recombinant fully humanized monoclonal IgG1 antibody against fibroblast growth factor 23 (FGF23) and is the world’s first drug approved for the treatment of XLH.

In a phase III clinical enrollment of 134 patients, a 1 mg/kg dose of either brusumab or placebo was randomly assigned 1:1, every 4 weeks for 24 weeks. After 24 weeks, patients from both groups continued to open the label test, during which time they received 1 mg/kg of Burusumab once every 4 weeks.

After 24 to 48 weeks of treatment, in patients receiving the treatment of brusumab (n = 68) since the start of the study, 84% achieved and maintained serum phosphorus levels above the lower limit of normal (2.5 mg/dL). 89% of patients who crossed from placebo to those who received 24 weeks of Burusumab treatment (n = 66) achieved and maintained serum phosphorus levels above the lower limit of normal.

9. Akynzeo (fosnetupitant /palonosetron)

Akynzeo is a compound intravenous injection of the palonosetron, a 5-HT3 receptor antagonist, and fosnetupitant, an NK-1 receptor antagonist, to prevent nausea and vomiting in cancer patients undergoing chemotherapy.

Palonosetron was approved in 2008 for the prevention of nausea and vomiting during the acute phase (within 24 hours) after the onset of cancer chemotherapy. Fosnetupitant is a new drug used to prevent nausea and vomiting during the acute and delayed phases (from 25 to 120 hours after chemotherapy) of cancer chemotherapy.

Fosnetupitant structure

On October 10, 2014, the FDA approved an oral capsule formulation developed by Helsinn and marketed under the trade name Akynzeo, a fixed-dose combination drug consisting of palonosetron and netupitant. The product is also a remission treatment for nausea and vomiting symptoms in cancer chemotherapy patients.

Netupitant structure

The effectiveness of Akynzeo was based on two clinical trials involving 1,720 subjects receiving cancer chemotherapy. Subjects were randomly injected with Akynzeo or oral palonosetron. The two trials were designed to test whether the study drug could prevent the onset of vomiting after the onset of cancer chemotherapy, the acute phase, the delayed phase, and the overall phase of chemotherapy. The first trial showed that 98.5%, 90.4%, and 89.6% of Akynzeo-treated subjects in the acute phase, delayed phase, and overall chemotherapy phase, respectively, did not experience vomiting or nausea requiring rescue medication. In contrast, 89.7%, 80.1%, and 76.5% of subjects in the oral, palonosetron-treated subjects who were in the acute phase, delayed phase, and overall chemotherapy phase, respectively, did not experience vomiting or nausea requiring rescue medication. The second experiment showed similar results.

10. Lucemyra(lofexidine hydrochloride)

Lucemyra is an oral selective α2-adrenoceptor agonist that reduces the release of norepinephrine. The role of norepinephrine in the autonomic nervous system is thought to play a role in many of the symptoms of opioid withdrawal. The FDA approved Lucemyra for the relief of withdrawal symptoms in adults after sudden withdrawal of opioids.

Lofexidine structure

Lucemyra’s safety and effectiveness were supported by two randomized, double-blind, placebo-controlled clinical trials. 866 adults who met the criteria for the IV Manual for Diagnosis and Statistics of Opioid Dependency participated in these clinical trials. The study evaluated the benefits of using SOWS-Gossop (short opioid dose or schedule) for assessing opioid withdrawal symptoms. Symptoms include feeling uncomfortable, stomach cramps, muscle cramps/convulsions, feeling cold, rapid heartbeat, muscle tension, pain, yawning, running tears, and insomnia/insomnia.

11. Aimovig (erenumab-aooe)

Aimovig is the first Calcitonin gene related peptide (CGRP) antibody drug approved by the FDA for the prevention of migraine in adults. Patients are self-administered once a month by subcutaneous injection.

The efficacy of Aimovig was confirmed in three clinical studies. The first study enrolled 955 patients with a history of intermittent attacks of migraines and compared the difference in efficacy between Aimovig and placebo. After 6 months of treatment, the average number of headaches per day in the treated group was 1 to 2 days less than the placebo group. The second study enrolled 577 patients with intermittent attacks of migraine. After 3 months of treatment, the average monthly number of headache attack days in the treatment group was 1 day less than that of placebo group; the third study included 667 patients with chronic migraine. In patients with a history of episodes, after 3 months of treatment, the average number of headache episodes per month in the dosing group was 2.5 days less than in the placebo group.

12. Lokelma(sodium zirconium cyclosilicate)

Lokelma (previously known as ZS-9, Zirconium Sodium Cyclamate) received FDA approval on May 18 after it was rejected by the FDA twice (for the first time in May 2015 and the second time in March 2017). Approved for the treatment of adult patients with hyperkalaemia. This is a serious disease manifested by elevated blood potassium levels associated with cardiovascular, renal and metabolic processes.

ZS-9 crystal structure

Lokelma was developed by ZS Pharmaceuticals. AstraZeneca acquired this potentially heavy drug after it acquired ZS Pharmaceuticals for US$2.7 billion in November 2015. Lokelma is considered as a best-in-class hyperkalemia treatment drug.

Lokelma is an insoluble, non-absorbing, novel selective cation exchanger designed to preferentially trap potassium ions. Approval was based on data from 3 double-blind, placebo-controlled studies and an open-label study. In these studies, patients with Lokalma treated hyperkalemia had a median blood potassium level of 2.2 hours, and up to 98% of patients achieved normal levels within 48 hours of treatment. In addition, Lokelma has also demonstrated control of serum potassium levels for up to one year.

13. Doptelet(avatrombopag)

Platelets are colorless cells produced in the bone marrow and help form blood clots in blood vessels to prevent bleeding. Thrombocytopenia is a condition in which the number of circulating platelets in the blood is lower than normal. Severe or life-threatening bleeding may occur when the patient’s platelet count is moderately or severely reduced, especially during invasive surgery. Patients with severe thrombocytopenia usually require platelet transfusion before surgery to increase platelet counts.

Doptelet (avatrombopag) is the second-generation, once-a-day, oral first thrombopoietin (TPO) receptor agonist. Doptelet mimics the effect of TPO, which is the main regulator of normal platelet production. The drug was given priority review to treat thrombocytopenia in adult CLD patients undergoing surgery.

Avatrombopag structural formula

Doptelet’s safety and effectiveness were validated in two trials (ADAPT-1 and ADAPT-2). These studies included a total of 435 patients with chronic liver disease and severe thrombocytopenia who would receive surgery that usually required infusion of platelets. These trials evaluated the effects of two dose levels of oral Doptelet compared to placebo for five days of treatment.

14. Palynziq(pegvaliase-pqpz)

PKU is a rare genetic disease that manifests itself at the time of birth and can cause various cumulative damage to the brain. In the United States, 1 in every 12,500 newborns is affected by PKU. PKU is manifested in patients unable to break down Phe, an amino acid found in all forms of protein. Without treatment, high levels of Phe can be toxic to the brain and can cause serious neurological and neuropsychiatric problems, affecting people’s thinking, feelings, and behavior.

Palynziq is a pegylated recombinant phenylalanine ammonia lyase that replaces Phenylalanine Hydroxylase (PAH), which is lacking in PKU patients, to decompose Phe.

The Palynziq effect was confirmed in clinical trials. In the key Phase III study PRISM-2, Palynziq significantly reduced blood Phe levels compared to placebo (p<0.0001), reaching the primary endpoint of blood Phe changes. In the PRISM-2 double-blind, placebo-controlled, randomized withdrawal trial (RWP), patients were randomly assigned to continue to receive Palynziq (20 mg daily or 40 mg daily) or placebo in a 2:1 ratio For 8 weeks. The results showed that patients in the Palynziq group were able to maintain blood Phe concentrations, whereas blood Phe concentrations in the placebo group returned to baseline before treatment.

15. Olumiant (baricitinib)

Rheumatoid arthritis is a type of arthritis that is chronic and prone to progress and is very painful. Currently, TNF inhibitors are common rheumatoid arthritis therapies, but about two-thirds of patients do not receive clinical remission from the first treatment. And over time, a large number of patients are unable to maintain the efficacy of the drug. Therefore, these patients urgently need an innovative drug to relieve the disease.

The new drug Olumiant (baricitinib), developed jointly by Lilly and Incyte, treats adult patients with moderate to severe rheumatoid arthritis but is unable to benefit from TNF inhibitor therapy.

Baricitinib structure

Olumiant is a once daily oral JAK inhibitor that efficiently inhibits JAK1, JAK2, and TYK2. In the human body, many cytokines are dependent on the activity of JAK, which has a potential role in the pathogenesis of many inflammatory diseases and autoimmune diseases. By inhibiting the activity of multiple JAKs, Olumiant is expected to bring a gospel to patients with rheumatoid arthritis.

16. Moxidectin (moxidectin)

Onchocercosis is the second leading cause of blindness in the world after trachoma. It is a species of lichenoid dermatitis, subcutaneous nodule and visual disturbance caused by parasitoids parasitic on human skin, subcutaneous tissue and eyes. Parasitic disease, also known as river blindness or filariasis.

On June 13, the FDA approved moxidectin for onchocercosis (river blindness) treatment in patients 12 years of age and older using 8 mg orally per day (four 2 mg tablets).

Moxidectin structure

Moxicotin is a novel antiparasitic drug, a single-component macrolide antibiotic obtained from the fermentation of Streptomyces. Its approval was mainly based on two clinical studies.

In trial 1, 978 patients received Moxidectin tablets in a single oral dose of 8 mg; 494 patients received a single oral dose of ivermectin of approximately 150 mcg/kg. In trial 2, 127 patients received Moxidectin tablets with a single oral dose ranging from 2 mg (this is not the approved dose) to 8 mg (38 received the recommended 8 mg dose) and 45 patients received a single dose of ivermectin Oral dose is approximately 150mcg/kg. The data show that moxectin has a significant advantage over current standard therapy (ivermectin) in inhibiting microfilaria in the skin.

17. Epidiolex (cannabidiol)

Lennox-Gastaut syndrome (LGS) is an age-related cryptogenic or symptomatic systemic epilepsy syndrome, a type of age-dependent epileptic encephalopathy. It is characterized by early onset of illness, early onset of onset, multiple seizures, and impaired intellectual development, making treatment difficult. Is a serious type of epilepsy.

Dravet syndrome (Dravet syndrome, DS), also known as severe myoclonic epilepsy in infants, is a rare and progressive epileptic encephalopathy caused by genetic factors. It has early age of onset, various attack types, and high frequency of epilepsy. Serious damage, poor drug treatment and other characteristics. The prognosis of the disease is poor, and almost all children have cognitive impairment.

The Epidiolex (Cannabidiol) [CBD] oral solution, approved by the FDA on June 25th, is a severe seizure that treats these two rare syndromes in patients 2 years of age and older.

Epidiolex is the first FDA-approved drug containing purified drugs extracted from cannabis, and is the first drug approved by the FDA to treat Dravet syndrome patients.

Cannabidiol structural formula

Epidiolex adjuvant therapy for the approval of LGS and DS-related epilepsy was based on data from three Phase III studies of safety and efficacy, each of which met the primary endpoint. Epidiolex is generally well tolerated in these studies. Epidiolex NDA includes safety data for approximately 1500 patients and data on approximately 400 consecutive patients treated for more than 1 year. In addition to key safety and efficacy data, the NDA also includes a comprehensive clinical pharmacology, preclinical, and toxicology data set.

18. Zemdri (plazomicin)

Zemdri (plazomicin) is used in adult patients with complex urinary tract infections (cUTI, including pyelonephritis) caused by certain Enterobacteriaceae bacterial infections with very limited or no treatment options. This drug is an intravenous drug Administer once daily.

Plazomicin structure

Zemdri’s approval was based on a cross-country, double-blind, non-inferiority trial in which a total of 609 adult patients with cUTI (including pyelonephritis) were randomly assigned to receive Zemdri (15 mg/kg IV once daily. 30 minutes infusion) and meropenem (intravenous injection of 1 g every 8 hours, 30 minutes infusion) treatment, compare the combined cure rate of both and eliminate the proportion of infected microorganisms. The results showed that patients treated with Zemdri had a significantly more comprehensive cure rate (81.7% vs. 70.1%) and eliminated the proportion of infected microorganisms (89.5% versus 74.6%) compared to the Meropenem group.

However, Zemdri’s BSI indication was rejected by the FDA because of a lack of validity in a clinical trial.

19~20. Braftiovi+Mektovi

Braftiovi (encorafenib) is an oral small molecule BRAF kinase inhibitor, and Mektovi (binimetinib) is an oral small molecule MEK inhibitor that targets a key enzyme in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Both drugs were developed by Array BioPharma.

Encorafenib structure

Binimetinib structure

 

The FDA approved Braftiovi and Mektovi combination therapy is based on the results of Phase III clinical trial COLUMBUS. Braftiovi+Mektovi doubled median progression-free survival (mPFS) compared to vemurafenib alone (7.3 months versus 14.9 months).

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