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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Omadacycline tosylate


1075240-43-5.pngChemSpider 2D Image | Omadacycline tosylate | C36H48N4O10S

Image result for Omadacycline tosylate

Omadacycline tosylate

728.8521, C29H40N4O7. C7H8O3S

CAS: 1075240-43-5

389139-89-3 FREE FORM

FDA 2018/10/3, Nuzyra

オマダサイクリントシル酸塩;

UNII-5658Y89YCD

(4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide 4-methylbenzenesulfonate (1:1)
1075240-43-5 [RN]
2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-9-[[(2,2-dimethylpropyl)amino]methyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S,4aS,5aR,12aS)-, 4-methylbenzenesulfonate (1:1) (salt)
5658Y89YCD
Amadacycline tosylate
PTK 0796 / PTK-0796
Omadacycline.svg
Omadacycline
FREE FORM, 389139-89-3 FREE FORM

Omadacycline has been used in trials studying the treatment of Bacterial Pneumonia, Bacterial Infections, Community-Acquired Infections, and Skin Structures and Soft Tissue Infections. Omadacycline represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings.

Omadacycline (formerly known as PTK-0796)[1] is a broad spectrum antibiotic belonging to the aminomethylcycline subclass[2] of tetracycline antibiotics. In the United States, it was approved in October 2018 for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

In vitro studies

In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negativepathogens.[3] Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), pencillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus. Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia.[4] This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.[5]

Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters.[6]

Mechanism of action

The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis. Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection).[7]

Clinical trials

phase 2 study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections. Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily. The results indicated that omadacycline is well-tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.[8]

In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.[9]

A 650 patient phase 3 registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015.[10][11]Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well-tolerated. The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).[12]

A 750 patient phase 3 study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015.[13] Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.[14]

In May 2016, a phase 1b study of omadacycline in urinary tract infection was initiated.[15]

In August 2016, a second phase 3 study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid.[16] In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met. This was the third phase 3 registration study of omadacycline with favorable results.[17]

Discovery

Omadacycline was invented at Tufts University School of Medicine by a research team led by Mark L. Nelson with Mohamed Ismail while at Tufts and Kwasi Ohemeng and Laura Honeyman at Paratek Pharmaceuticals, Boston. The team applying their chemistry methods to the tetracycline scaffolds created over 3000 new derivatives, leading to the novel third generation compounds omadacycline and sarecycline18[18]

PAPERS

Tetrahedron Letters (2008), 49(42), 6095-6100

str1

PATENTS

WO 2009120389

WO 2009111064

WO 2017165729

WO 2018026987

WO 2018085216

SYNTHESIS BY PHARMACODIA WEBSITE

Omadacyclinewww.pharmacodia.com

Image result for Omadacycline tosylate

Image result for Omadacycline tosylate

Image result for Omadacycline tosylate

REF Omadacyclinewww.pharmacodia.com

Route 3

References

  1. Jump up^ Boggs, Jennifer. “Antibiotic Firm Paratek Joins IPO Queue; Aiming for $92M”bioworld.com. Clarivate Analytics. Retrieved October 17, 2017.
  2. Jump up^ Honeyman, Laura; Ismail, Mohamed; Nelson, Mark L.; Bhatia, Beena; Bowser, Todd E.; Chen, Jackson; Mechiche, Rachid; Ohemeng, Kwasi; Verma, Atul K.; Cannon, E. Pat; MacOne, Ann; Tanaka, S. Ken; Levy, Stuart (2015). “Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline”Antimicrobial Agents and Chemotherapy59 (11): 7044–7053. doi:10.1128/AAC.01536-15PMC 4604364PMID 26349824.
  3. Jump up^ Tanaka, S. Ken (20 June 2016). “In Vitro and In Vivo Assessment of Cardiovascular Effects with Omadacycline”Antimicrobial Agents and Chemotherapy60 (9): 5247–53. doi:10.1128/AAC.00320-16PMC 4997885PMID 27324778.
  4. Jump up^ Villano, Stephen (19 August 2016). “Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections”Future Microbiology11: 1421–1434. doi:10.2217/fmb-2016-0100. Retrieved 24 August 2016.
  5. Jump up^ MacOne, A. B.; Caruso, B. K.; Leahy, R. G.; Donatelli, J.; Weir, S.; Draper, M. P.; Tanaka, S. K.; Levy, S. B. (February 2014). “In Vitro and in Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline”Antimicrobial Agents and Chemotherapy58 (2): 1127–1135. doi:10.1128/AAC.01242-13PMC 3910882PMID 24295985.
  6. Jump up^ Flarakos, Jimmy (8 August 2016). “Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline”Xenobiotica: 1–15. doi:10.1080/00498254.2016.1213465.
  7. Jump up^ Draper, M. P.; Weir, S.; MacOne, A.; Donatelli, J.; Trieber, C. A.; Tanaka, S. K.; Levy, S. B. (March 2014). “Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline”Antimicrobial Agents and Chemotherapy58 (3): 1279–1283. doi:10.1128/AAC.01066-13PMC 3957880PMID 24041885.
  8. Jump up^ Noel, G. J.; Draper, M. P.; Hait, H.; Tanaka, S. K.; Arbeit, R. D. (November 2012). “A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Efficacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections”Antimicrobial Agents and Chemotherapy56 (11): 5650–5654. doi:10.1128/AAC.00948-12PMC 3486554PMID 22908151.
  9. Jump up^ “Paratek Pharmaceuticals Announces FDA Grant of Qualified Infectious Disease Product (QIDP) Designation for Its Lead Product Candidate, Omadacycline”prnewsire.com. PR Newswire. January 3, 2013. Retrieved October 17, 2017.
  10. Jump up^ Seiffert, Don (2015). “Paratek presents new trial data for antibiotic as late-stage trials continue”bizjournals.com. American City Business Journals. Retrieved October 17,2017.
  11. Jump up^ “Omadacycline Versus Linezolid for the Treatment of ABSSSI (EudraCT #2013-003644-23)”clinicaltrials.gov. Retrieved 2015-10-13.
  12. Jump up^ “Paratek Announces that Omadacycline Met All Primary and Secondary Efficacy Outcomes Designated by FDA and EMA in a Phase 3 Study in Acute Bacterial Skin Infections; Omadacycline was Generally Safe and Well-Tolerated”finance.yahoo.com. Retrieved 3 July 2016.
  13. Jump up^ “Omadacycline vs Moxifloxacin for the Treatment of CABP (EudraCT #2013-004071-13)”clinicaltrials.gov. Retrieved 2015-10-13.
  14. Jump up^ “Paratek Announces Positive Phase 3 Study of Omadacycline in Community-Acquired Bacterial Pneumonia”http://www.globenewswire.com. April 3, 2017. Retrieved 16 May 2017.
  15. Jump up^ “Paratek Initiates Phase 1b Study of Omadacycline in Urinary Tract Infection”globenewswire.com. May 2, 2016. Retrieved 3 July 2016.
  16. Jump up^ “Paratek Initiates Phase 3 Study of Oral-only Omadacycline in ABSSSI”globenewswire.com. August 15, 2016. Retrieved 15 August 2016.
  17. Jump up^ “Paratek Announces Phase 3 Study of Oral-Only Dosing of Omadacycline Met All Primary and Secondary FDA and EMA Efficacy Endpoints in Acute Bacterial Skin Infections”http://www.globenewswire.com. July 17, 2017. Retrieved 19 July 2017.
  18. Jump up^ Ref: Mark L. Nelson and Kwasi Ohemeng: 4-dedimethylamino tetracycline compounds, United States (US) patent number 7,056,902 (2006)
Omadacycline
Omadacycline.svg
Clinical data
Trade names Nuzyra
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C29H40N4O7
Molar mass 556.66 g·mol−1
3D model (JSmol)

/////////////FDA 2018, Nuzyra, Omadacycline tosylate, Omadacycline, オマダサイクリントシル酸塩 ,PTK-0796, PTK 0796

CC1=CC=C(C=C1)S(O)(=O)=O.[H][C@@]12CC3=C(C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)N(C)C

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FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


 

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

 

November 28, 2018

Release

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review,  Breakthrough Therapy,  Firdapse,  Orphan Drug designation, fda 2018, amifampridine

FDA approves new treatment for patients with acute myeloid leukemia


FDA approves new treatment Daurismo (glasdegib) for patients with acute myeloid leukemia 
The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.
“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that  ..

November 21, 2018

Release

The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.

“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of Daurismo was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either Daurismo in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with Daurismo. The median OS was 8.3 months for patients treated with Daurismo plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving Daurismo in clinical trials include low red blood cell count (anemia), tiredness (fatigue), bleeding (hemorrhage), fever with low white blood cell count (febrile neutropenia), muscle pain, nausea, swelling of the arms or legs (edema), low platelet counts (thrombocytopenia), shortness of breath (dyspnea), decreased appetite, distorted taste (dysgeusia), pain or sores in the mouth or throat (mucositis), constipation and rash.

The prescribing information for Daurismo includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. Daurismo should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of Daurismo treatment and effective contraception should be used during treatment and for at least 30 days after the last dose. The Boxed Warning also advises male patients of the potential risk of drug exposure through semen and to use condoms with a pregnant partner or a female partner that could become pregnant both during treatment and for at least 30 days after the last dose. Daurismo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Daurismo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Daurismo to Pfizer.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626443.htm?utm_campaign=112118_PR_FDA%20approves%20new%20treatment%20for%20patients%20with%20acute%20myeloid%20leukemia&utm_medium=email&utm_source=Eloqua

//////////////Daurismo, glasdegib, fda 2018, Priority Review, Orphan Drug 

FDA approves first treatment Gamifant (emapalumab) specifically for patients with rare and life-threatening type of immune disease


FDA approves first treatment Gamifant (emapalumab)  specifically for patients with rare and life-threatening type of immune disease 

The U.S. Food and Drug Administration today approved Gamifant (emapalumab) for the treatment of pediatric (newborn and above) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. This FDA approval is the first for a drug specifically for HLH.

“Primary HLH is a rare and life-threatening condition typically affecting children and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of therapies that offer meaningful treatment options for 

November 20, 2018

Release

The U.S. Food and Drug Administration today approved Gamifant (emapalumab-lzsg) for the treatment of pediatric (newborn and above) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. This FDA approval is the first for a drug specifically for HLH.

“Primary HLH is a rare and life-threatening condition typically affecting children and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of therapies that offer meaningful treatment options for patients with rare conditions.”

HLH is a condition in which the body’s immune cells do not work properly. The cells become overactive releasing molecules, which leads to inflammation. The immune cells start to damage the body’s own organs, including the liver, brain and bone marrow. It can be inherited, which is known as primary or “familial” HLH. It can also have non-inherited causes. People with primary HLH usually develop symptoms within the first months or years of life. Symptoms may include fever, enlarged liver or spleen and decreased number of blood cells.

The efficacy of Gamifant was studied in a clinical trial of 27 pediatric patients with suspected or confirmed primary HLH with either refractory, recurrent or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy. The median age of the patients in the trial was 1 year old. The study showed that 63 percent of patients experienced a response and 70 percent were able to proceed to stem cell transplant.

Common side effects reported by patients receiving Gamifant in clinical trials included infections, hypertension, infusion-related reactions, low potassium and fever. Patients receiving Gamifant should not receive any live vaccines and should be tested for latent tuberculosis. Patients should be closely monitored and treated promptly for infections while receiving Gamifant.

The FDA granted this application Priority Review and Breakthrough Therapydesignation. Gamifant also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Gamifant to Novimmune SA.

LINK https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM626263.htm?utm_campaign=112018_PR_FDA%20approves%20treatment%20for%20patients%20with%20HLH%20l&utm_medium=email&utm_source=Eloqua

////////////Gamifant, emapalumab, FDA 2018

FDA approves new drug Aemcolo (rifamycin), to treat travelers’ diarrhea


FDA approves new drug to treat travelers’ diarrhea
The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.
“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by …

November 16, 2018

Release

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP)designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted approval of Aemcolo to Cosmo Technologies, Ltd.

///////////////// Aemcolo, rifamycin, fda 2018, qidp, priority review

FDA approves a new drug Xofluza (baloxavir marboxil) to treat influenza


Today, the U.S. Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

October 24, 2018

Release

Español

Today, the U.S. Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

“This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option,” said FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they’re not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.”

Flu is a contagious respiratory illness caused by influenza viruses. When patients with the flu are treated within 48 hours of becoming sick, antiviral drugs can reduce symptoms and duration of the illness.

“When treatment is started within 48 hours of becoming sick with flu symptoms, antiviral drugs can lessen symptoms and shorten the time patients feel sick,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.”

The safety and efficacy of Xofluza, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 patients where participants were assigned to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.

The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis.

Xofluza was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted approval of Xofluza to Shionogi & Co., Ltd.

//////////////Xofluza, baloxavir marboxil, FDA 2018

USFDA approval to Lumoxiti (moxetumomab pasudotoxtdfk) a new treatment for hairy cell leukemia


Image result for moxetumomab pasudotox tdfk

USFDA approval to Lumoxiti is a new treatment for hairy cell leukemia

On September 13, 2018, the U.S. Food and Drug Administration approved Lumoxiti (moxetumomab pasudotoxtdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory Hairy Cell Leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog 1. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals. About Hairy Cell Leukemia HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cells that fight infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

About Lumoxiti2 Lumoxiti (moxetumomab pasudotox) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

1 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm

2 https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-lumoxiti-moxetumomab-pasudotox-tdfk-for-certain-patientswith-relapsed-or-refractory-hairy-cell-leukaemia.html

/////////// Lumoxiti, moxetumomab pasudotoxtdfk, FDA 2018, Fast Track,  Priority Review ,  Orphan Drug, AstraZeneca

FDA approves first treatment Libtayo (cemiplimab-rwlc) for advanced form of the second most common skin cancer


FDA approves first treatment for advanced form of the second most common skin cancer

New drug targets PD-1 pathway

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

September 28, 2018

Release

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

Libtayo works by targeting the cellular pathway known as PD-1 (protein found on the body’s immune cells and some cancer cells). By blocking this pathway, the drug may help the body’s immune system fight the cancer cells.

“We’re continuing to see a shift in oncology toward identifying and developing drugs aimed at a specific molecular target. With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This type of cancer can be difficult to treat effectively when it is advanced and it is important that we continue to bring new treatment options to patients.”

CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases. The most common form of skin cancer is basal cell cancer. Squamous cells are thin, flat cells that look like fish scales and are found in the tissue that forms the surface of the skin. CSCC usually develops in skin areas that have been regularly exposed to the sun or other forms of ultraviolet radiation. While the majority of patients with CSCC are cured with surgical resection, a small percentage of patients will develop advanced disease that no longer responds to local treatments including surgery and radiation. Advanced CSCC may cause disfigurement at the site of the tumor and local complications such as bleeding or infection, or it may spread (metastasize) to local lymph nodes, distant tissues and organs and become life-threatening.

The safety and efficacy of Libtayo was studied in two open label clinical trials. A total of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the efficacy evaluation. The study’s primary endpoint was objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment. Results showed that 47.2 percent of all patients treated with Libtayo had their tumors shrink or disappear. The majority of these patients had ongoing responses at the time of data analysis.

Common side effects of Libtayo include fatigue, rash and diarrhea. Libtayo must be dispensed with a patient Medication Guide that describes uses of the drug and its serious warnings. Libtayo can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These reactions can sometimes become severe or life-threatening and can lead to death. These reactions include the risk of immune-mediated adverse reactions including lung problems (pneumonitis), intestinal problems (colitis), liver problems (hepatitis), hormone gland problems (endocrinopathies), skin (dermatologic) problems and kidney problems. Patients should also be monitored for infusion-related reactions.

Libtayo can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignations.

The FDA granted the approval of Libtayo to Regeneron Pharmaceuticals, Inc.

////////////Libtayo, cemiplimab-rwlc, FDA 2018,  Breakthrough Therapy,  Priority Review

Sarecycline , サレサイクリン


Sarecycline.svg

ChemSpider 2D Image | Sarecycline | C24H29N3O8

Sarecycline

サレサイクリン

MW 487.5024, MF C24H29N3O8 FREE FORM

Paratek  INNOVATOR

FDA 2018/10/1 APPROVED SEYSARA, ALMIRALL, for the oral treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older

(4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-{[methoxy(methyl)amino]methyl}-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide
1035654-66-0 [RN] FREE FORM
2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-, (4S,4aS,5aR,12aS)-
94O110CX2E
9743

P005672, 

  • P 005672

Sarecycline hydrochloride.png

CAS 1035979-44-2 HCl

Molecular Formula C24 H29 N3 O8 . Cl H
 Molecular Weight 523.963

P-005672
PTK-AR-01
SC-1401
WC-3035

Sarecycline (trade name Seysara; development code WC-3035) is a tetracycline-derived antibiotic. In the United States, it was approved by the FDA in October 2018 for the treatment of moderate to severe acne vulgaris.[1]

Paratek Pharmaceuticals, Inc. licensed the US rights to sarecycline for the treatment of acne in the United States to Actavis, a subsidiary of Allergan, while retaining rights in the rest of the world.[2]

Allergan initiated a Phase 3 study in December 2014 evaluating the efficacy and safety of sarecycline tablets 1.5 mg/kg per day taken orally for 12 weeks versus placebo in the treatment of acne vulgaris.[3] Two phase 3 randomized, multi-center, double-blind, placebo-controlled studies evaluating the efficacy and safety of sarecycline in moderate to severe acne reported positive results on 27 March 2017.[4]

SYN

US 2016/0200671

PATENT

WO 2008079363

PATENT

WO 2008079339

PATENT

WO 2012155146

EXAMPLES

[00104] The following examples illustrate the synthesis of the compounds described herein.

Synthesis of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (“the free base”).

[00105] A solution of 7-formylsancycline TFA salt (2.23 g) and N,0-dimethylhydroxylamine hydrochloride (780 mg) in N,N-dimethylacetamide (15 mL) was stirred for 10 minutes at room temperature under argon atmosphere. To this solution was added sodium cyanoborohydride (302 mg). The solution was stirred for 5 minutes and monitored by LC-MS. The reaction mixture was poured into diethyl ether, and the resulting precipitates were collected by filtration under vacuum. The crude product was purified by prep-HPLC using a C18 column (linear gradient 10-40% acetonitrile in 20 mM aqueous triethanolamine, pH 7.4). The prep-HPLC fractions were collected, and the organic solvent (acetonitrile) was evaporated under reduced pressure. The resulting aqueous solution was loaded onto a clean PDVB SPE column, washed with distilled water, then with a 0.1 M sodium acetate solution followed by distilled water. The product was eluted with

acetonitrile. The eluent was concentrated under reduced pressure, 385 mg was obtained as free base.

Synthesis of crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (the “Crystalline Mono Hydrochloride Salt”).

[00106] Crude (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l ,ll-dioxo-l,4,4a,5,5a,6,l l ,12a-octahydro-naphthacene-2-carboxylic acid amide (lOOg, app. 35% assay) was purified on preparative column chromatography. The desired fractions (8-10 liters) were combined and the pH was adjusted to 7.0-7.5 using ammonium hydroxide. This aqueous solution was extracted 3 times with dichloromethane (4 liters each time). The dichloromethane layers were combined and concentrated under reduced pressure. The residue was suspended in ethanol (800 ml) and 20 ml water was added. The pH was gradually adjusted to pH 1.6-1.3 using 1.25M hydrochloric acid in methanol and the mixture was stirred for 20-60 minutes at which point the free base was completely dissolved. The solution was concentrated under reduced pressure to 200-250 ml and was seeded with (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono HQ crystals (100-200 mg). The stirring was continued for 2-18 hours while the slurry was kept at <5°C. The resulting crystals were filtered, washed with ethanol (50 mL) and dried under reduced pressure to a constant weight. 20g crystalline (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono hydrochloride was isolated in > 90% purity and > 90% assay.

Synthesis of crystalline mono mesylate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Mesylate Salt”).

[00107] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (74mg) was suspended in ethanol (740μ1) and heated with stirring to 60°C (bath temperature). Methane sulfonic acid (1.1 eq, 167μ1 as 1M solution in THF) was added and most of the solid dissolved. After five minutes, the suspension was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath). By 53 °C, solid had precipitated which was filtered at ambient temperature under reduced pressure. A further portion of ethanol (200μ1) was added to aid filtration, as the suspension was viscous. The cake was washed with n-hexane (400μ1) and air dried on filter for approximately 30 minutes to yield 59 mg (67% yield) of yellow solid.

Synthesis of crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Sulfate Salt”).

[00108] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (86mg) was suspended in ethanol (500μ1) and heated with stirring to 63 °C (bath temperature) at which temperature most of the free base had dissolved. Sulfuric acid (1.1 eq, 194μ1 as 1M solution in water) was added and all of the solid dissolved. The solution was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath) at which temperature no solid had precipitated. Methyl t-butyl ether (MtBE) was added as an antisolvent (4 x 50μ1). Each addition caused a cloud point, but the solid re-dissolved on stirring. The solution was stirred with a stopper for approximately 3 hours after which time solid precipitated. The solid was filtered under reduced pressure and washed with MtBE (3 x 200μ1) and air dried on filter for

approximately 45 minutes to yield 93 mg (90% yield) of yellow solid.

COMPARATIVE EXAMPLE 1

Synthesis of amorphous bis hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00109] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (1 g) was suspended in methanol (50 mL). The freebase was converted to the hydrochloride salt by adding an excess of methanolic HCl followed by under reduced pressure evaporation to give 1.1 g yellow solid: MS (Mz+1 = 488). 1H NMR (300 MHz, CD30D) δ 7.46 (d, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 8.6 Hz), 4.09 (d, 1H, J = 1.0 Hz), 3.79 (d, 1H, J = 13.1 Hz), 3.73 (d, 1H, J = 13.1 Hz), 3.36 (m, 1H), 3.27 (s, 3H), 3.08-2.95 (8H), 2.61 (s, 3H), 2.38 (t, 1H, J = 14.8), 2.22 (m, 1H), 1.64 (m, 1H). An XRPD pattern is shown in Figure 10 and a TGA and DSC curve overlaid are shown in Figure 11.

COMPARATIVE EXAMPLE 2

Synthesis of amorphous mono hydrochloride salt of (4S,4aS,5aR,12aS)-4- dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll- dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00110] A sample of Crystalline Mono Hydrochloride Salt (2.09 g) was dissolved in water (250 ml, 120 vols), filtered and frozen in a -78°C bath. Water was removed from the solidified sample using a lyophilizer for 110 hours to yield the amorphous mono hydrochloride salt as a fluffy yellow solid, that was confirmed to be amorphous by XRPD analysis .

PATENT

US 20130302442

PATENT

WO 2015153864

PATENT

WO 2018051102

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003075857

References

External links

Sarecycline
Sarecycline.svg
Clinical data
Trade names Seysara
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C24H29N3O8
Molar mass 487.51 g·mol−1
3D model (JSmol)

////////////Sarecycline, Seysara, WC-3035 FDA 2018, サレサイクリン , P-005672 , PTK-AR-01 , SC-1401, WC-3035,

FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation


FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation

First drug granted approval under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, instituted to spur development of antibiotics for unmet medical needs

The U.S. Food and Drug Administration today approved a new drug, Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease).

MAC is a type of nontuberculous mycobacteria (NTM) commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

September 28, 2018

Release

The U.S. Food and Drug Administration today approved a new drug, Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease).

MAC is a type of nontuberculous mycobacteria (NTM) commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

“As bacteria continue to grow impervious to currently available antibiotics, we need to encourage the development of drugs that can treat resistant infections. That means utilizing novel tools intended to streamline development and encourage investment into these important endeavors,” said FDA Commissioner Scott Gottlieb, M.D. “This approval is the first time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, and it marks an important policy milestone. This pathway, advanced by Congress, aims to spur development of drugs targeting infections that lack effective therapies. We’re seeing a lot of early interest among sponsors in using this new pathway, and it’s our hope that it’ll spur more development and approval of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.”

Arikayce is the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway, established by Congress under the 21st Century Cures Act to advance development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Approval under the LPAD pathway may be supported by a streamlined clinical development program. These programs may involve smaller, shorter or fewer clinical trials. As required for drugs approved under the LPAD pathway, labeling for Arikayce includes certain statements to convey that the drug has been shown to be safe and effective only for use in a limited population.

Arikayce also was approved under the Accelerated Approval pathway. Under this approach, the FDA may approve drugs for serious or life-threatening diseases or conditions where the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The approval of Arikayce was based on achieving three consecutive negative monthly sputum cultures by month six of treatment. The sponsor of Arikayce will be required by the FDA to conduct an additional, post-market study to describe the clinical benefits of Arikayce.

The safety and efficacy of Arikayce, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received Arikayce plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29 percent of patients treated with Arikayce had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with Arikayce.

The Arikayce prescribing information includes a Boxed Warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking Arikayce were dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

The FDA granted this application Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product (QIDP) designations. QIDP designation is given to antibacterial products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. Arikayce also received Orphan Drug designation, which provides additional incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Arikayce to Insmed, Inc. of Bridgewater, NJ.

/////////////////// Arikayce, amikacin liposome inhalation suspension, fda 2018, Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product, QIDP, Generating Antibiotic Incentives Now, GAIN,
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