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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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FDA approves new uses for two drugs Tafinlar (dabrafenib) and Mekinist (trametinib) administered together for the treatment of BRAF-positive anaplastic thyroid cancer


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FDA approves new uses for two drugs Tafinlar (dabrafenib) and Mekinist (trametinib) administered together for the treatment of BRAF-positive anaplastic thyroid cancer

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive). Continue reading.

May 4, 2018

Release

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” 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 approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.

Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.

Both Tafinlar and Mekinist 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 Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

 

///////////////Tafinlar, dabrafenib,  Mekinist, trametinib, fda 2018, Priority Review,  Breakthrough Therapy designation, Orphan Drug designation,  Novartis Pharmaceuticals Corporation,

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FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options


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FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk),for patients who have limited treatment options

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.

 

 

March 6, 2018

Release

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.

“While most patients living with HIV can be successfully treated using a combination of two or more antiretroviral drugs, a small percentage of patients who have taken many HIV drugs in the past have multidrug resistant HIV, limiting their treatment options and putting them at a high risk of HIV-related complications and progression to death,” said Jeff Murray, M.D., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Trogarzo is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options. New treatment options may be able to improve their outcomes.”

The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.

The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of Trogarzo in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the Trogarzo development program.

A total of 292 patients with HIV-1 infection have been exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The FDA granted this application Fast TrackPriority Review and Breakthrough Therapy designations. Trogarzo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Trogarzo to TaiMed Biologics USA Corp.

Theratechnologies Announces FDA Approval of Breakthrough Therapy, Trogarzo™ (ibalizumab-uiyk) Injection, the First HIV-1 Inhibitor and Long-Acting Monoclonal Antibody for Multidrug Resistant HIV-1


NEWS PROVIDED BY

Theratechnologies Inc. 


  •  First HIV treatment approved with a new mechanism of action in more than 10 years
  • Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
  • Trogarzo™ has no drug-drug interactions and no cross-resistance with other ARTs

MONTREALMarch 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo™ (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo™ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.1

Trogarzo™ represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo™ is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.1

“Today’s approval of Trogarzo™ by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo™, and are helping address this critical unmet medical need.”

Trogarzo™ previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.

“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”

Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.13

“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo™ patient. “Since starting treatment with Trogarzo™ six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo™ is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”

TaiMed and Theratechnologies partnered on the development of Trogarzo™ so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo™ or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support™ at 1-833-23-THERA (84372).

“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”

Clinical Trial Findings

Clinical studies show that Trogarzo™, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.

The Phase 3 trial showed:1

  • Trogarzo™ significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
  • More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log10 (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo™ and no adjustment to the failing background regimen.
  • The average viral load reduction after 24 weeks was 1.6 log10 with 43% of patients achieving undetectable viral loads.

Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm3, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.1

The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.1

About Trogarzo™ (ibalizumab-uiyk) Injection

Trogarzo™ is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo™ binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.

IMPORTANT SAFETY INFORMATION

Trogarzo™ is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.

Trogarzo™ blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.

Before you receive Trogarzo™, tell your healthcare provider if you:

  • are pregnant or plan to become pregnant. It is not known if Trogarzo™ may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Trogarzo™ passes into breast milk.

Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.

Trogarzo™ can cause serious side effects, including:

Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines.  Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time.  Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of Trogarzo™ include:

  • Diarrhea
  • Dizziness
  • Nausea
  • Rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo™. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  You may also report side effects to at 1-833-23THERA (1-833-238-4372).

 

About Theratechnologies

Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.

/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast TrackPriority Review, Breakthrough Therapy designations,  Orphan Drug designation

Acalabrutinib, ACP-196, Акалабрутиниб , أكالابروتينيب , 阿可替尼 ,


ChemSpider 2D Image | acalabrutinib | C26H23N7O2

Acalabrutinib.png

Image result for Acalabrutinib

Acalabrutinib

  • Molecular FormulaC26H23N7O2
  • Average mass465.507 Da

AcalabrutinibrINN, ACP-196,

FDA 2017 APPROVED, Lymphoma, mantle cell, ACERTA PHARMA

Orphan Drug, breakthrough therapy designation,

CAS 1420477-60-6 [RN]

(S)-4-[8-Amino-3-[1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(pyridin-2-yl)benzamide

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

4-{8-Amino-3-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide
Benzamide, 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-
Calquence [Trade name]
UNII:I42748ELQW
Акалабрутиниб [Russian] [INN]
أكالابروتينيب [Arabic] [INN]
阿可替尼 [Chinese] [INN]
4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-benzamide
4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide
I42748ELQW
Image result for Acalabrutinib
Image result for Acalabrutinib
 Acalabrutinib, also known as ACP-196, is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, ACP-196 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.
Image result for Acalabrutinib

Acalabrutinib (rINN,[1] ACP-196) is a novel experimental anti-cancer drug and a 2nd generation Bruton’s tyrosine kinase (BTK) inhibitor[2][3] developed by Acerta Pharma.[4] It is more potent and selective (fewer side-effects) than ibrutinib, the first-in-class BTK inhibitor.[2][3][5]

The compound was granted orphan drug designation for the treatment of chronic lymphocytic leukemia, Waldenström’s macroglobulinemia and mantle cell lymphoma in the U.S. and the E.U. in 2015 and 2016, respectively. In 2017, the product was granted breakthrough therapy designation in the U.S. for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Acalabrutinib is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, acalabrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosinekinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

Acalabrutinib is a Bruton’s Tyrosine Kinase (BTK) inhibitor developed at Acerta Pharma launched in 2017 in the U.S. for the oral treatment of adults with mantle cell lymphoma who have received at least one prior therapy.

Image result for Acalabrutinib

Image result for Acalabrutinib

To date, acalabrutinib has been used in trials studying the treatment of B-All, Myelofibrosis, Ovarian Cancer, Multiple Myeloma, and Hodgkin Lymphoma, among others. As of October 31, 2017 the FDA approved Astra Zeneca’s orally administered Calquence (acalabrutinib) medication as a Bruton Tyrosine Kinase (BTK) inhibitor indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have already received at least one prior therapy, marking the company’s first entry into the treatment of blood cancers. Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK. Nevertheless, acalabrutinib was approved under the FDA’s accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib’s currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials. Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib [L1009].
Image result for Acalabrutinib

Clinical and Regulatory Status

Pre-clinical

Relative to ibrutinib, acalabrutinib demonstrated higher selectivity and inhibition of the targeted activity of BTK, while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.[3] In addition, in platelets treated with ibrutinib, thrombus formation was clearly inhibited while no impact to thrombus formation was identified relative to controls for those treated with acalabrutinib.[3] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib.[3]

As was conducted in the development of ibrutinib, pre-clinical studies of acalabrutinib included in vitro and in vivo pharmacodynamic evaluation in a canine lymphoma model.[6] A dose-dependent relationship resulting in cyto-toxicity and anti-proliferative effects was first demonstrated in a canine lymphoma cell line in vitro.[6] In vivo, the compound was found to be generally safe and well tolerated in the dosage range of 2.5–20 mg/kg every 12 or 24 hours, with clinical benefit observed in 30% of canine patients while observed adverse events consisted primarily of gastrointestinal effects such as anorexia, weight loss, vomiting, diarrhea and lethargy.[6]

Image result for Acalabrutinib

Clinical

The interim results of the still on-going first human phase 1/2 clinical trial (NCT02029443) with 61 patients for the treatment of relapsed chronic lymphocytic leukemia (CLL) are encouraging, with a 95% overall response rate demonstrating potential to become a best-in-class treatment for CLL.[2][7] Notably, a 100% response rate was achieved for those patients which were positive for the 17p13.1 gene deletion – a subgroup of patients that typically results in a poor response to therapy and expected outcomes.[3]

The most common adverse events were headache, diarrhea and weight gain.[3] Despite the appearance of a greater occurrence of transient headaches, the pre-clinical data suggests a preferred advantage of acalabrutinib over ibrutinib due to expected reduced adverse events of skin rash, severe diarrhea, and bleeding risk.[3] An additional clinical trial is currently in progress to directly compare the safety and efficacy performance of acalabrutinib to ibrutinib to better elucidate the differences in the therapeutic agents.[3]

While the primary indication is for CLL, as of late 2016, acalabrutinib is under evaluation for multiple indications in 20+ clinical trials (alone and in combination with other interventions) for various blood cancers, solid tumors, and rheumatoid arthritis.[7][8] Approximately 1,000 patients have been treated with acalabrutinib in clinical trials so far, including more than 600 on acalabrutinib alone and almost 400 on additional therapies in combination with acalabrutinib.[9]

Regulatory

As of February 2016, acalabrutinib had received orphan designation in the United States for CLL only,[10] and was similarly designated as an orphan medicinal product by the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) for treatment of three indications – chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and lymphoplasmacytic lymphoma (Waldenström’s macroglobulinaemia, MG).[11] If the drug is ultimately approved, this designation will result in a 10-year period of market exclusivity for the stated indications within Europe.[12]

Commercial Aspects

Acerta Pharma, the innovator responsible for the discovery and development of acalabrutinib, is a clinical stage biopharmaceutical company recently founded in 2012 in Oss, the Netherlands.[13] A combined $13 Million in Series A funding was secured March 14, 2013 from various investor sources including the venture capital firms of BioGeneration Ventures and OrbiMed Advisors, the Dutch State and Province of Brabant through the Brabant Development Agency, and the private US equity firm Frazier Healthcare.[14] Further undisclosed amounts of Series B funding was secured May 2015 from the mutual fund company T. Rowe Price.[15]

After the promising results for the treatment of CLL in initial clinical trials,[2] Astra Zeneca purchased a 55% stake in Acerta Pharma for $4 billion in December 2015, with an option to acquire the remaining 45% stake for an additional $3 billion, conditional on the first approval in both the US and Europe and the establishment of commercial opportunity.[16]

Intellectual Property

Several patents have been filed by Acerta Pharma through the World Intellectual Property Organization (WIPO) for the use of acalabrutinib (and structurally similar derivatives) either alone or in combination with additional therapeutic agents for the treatment of various hematological and solid tumor cancers as well as inflammatory and autoimmune diseases.[17][18][19][19][20][21][22][23][24][25][26][27]

Notably, patents filed through WIPO still need to be filed appropriately for each individual nation on the path to commercialization. For example, one related United States patent application is US2014155385, which was filed July 11, 2012 and approved June 5th, 2014 for the use of 6-5 membered fused pyridine ring compounds (including acalabrutnib and its structurally similar derivatives) in the treatment of BTK mediated disorders.[28]

SYNTHESIS

Inventors Tjeerd A. BarfChristiaan Gerardus Johannes Maria Jansde Adrianus Petrus Antonius MANArthur A. OubrieHans C.A. RaaijmakersJohannes Bernardus Maria RewinkelJan-Gerard SterrenburgJacobus C.H.M. Wijkmans
Applicant Msd Oss B.V.

WO 2013010868

Synthesis of acalabrutinib, using 3-chloropyrazine-2-carbonitrile as the starting material, is described. The method comprises reduction of the starting material, condensation with N-Cbz-L-proline, intramolecular cyclization, bromination, Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid and condensation with 2-butynoic acid. WO 2013010868

Reduction of 3-chloropyrazine-2-carbonitrile  with H2 over Raney-Ni in AcOH, followed by treatment with aqueous HCl in Et2O gives (3-chloro-2-pyrazinyl)methylamine hydrochloride , which upon condensation with N-Cbz-L-proline  in the presence of HATU and Et3N in CH2Cl2 affords amide .

Intramolecular cyclization of intermediate  by means of DMI and POCl3 in acetonitrile at 63 °C provides N-Cbz-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine , which is brominated with NBS in DMF to yield N-Cbz-1-bromo-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine .

Reaction of chloro compound  with NH3 in i-PrOH at 110 °C produces N-Cbz-1-bromo-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine , which upon Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid in the presence of PdCl2(dppf) and K2CO3 in dioxane at 140 °C under microwave irradiation furnishes diaryl derivative .

Removal of the benzyloxycarbonyl moiety in intermediate  using HBr in AcOH generates pyrrolidine derivative , which is condensed with 2-butynoic acid  in the presence of HATU and Et3N in CH2Cl2 to afford the target acalabrutinib 

PATENT

WO 2013010868

https://www.google.com/patents/WO2013010868A1?cl=en

scheme I

Figure imgf000026_0001

 scheme II

Figure imgf000027_0001

Intermediate 1

Figure imgf000032_0001

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-vnpyrrolidine-1-carboxylate

(a) (3-Chloropyrazin-2-yl)methanamine. hydrochloride

To a solution of 3-chloropyrazine-2-carbonitrile (160 g, 1 .147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50°C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1 .14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C. The product brown solid obtained was dissolved in methanol at 60°C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C to give 153.5 g of (3-chloropyrazin-2- yl)methanamine. hydrochloride as a brown solid (74.4 %, content 77 %).

(b) (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate

To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21 .26 mmol) in dichloromethane (250 mL) was added triethylamine (1 1.85 mL, 85 mmol) and the reaction mixture was cooled to 0°C. After 15 min stirring at 0°C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0°C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).

(c) (S)-Benzyl 2-(8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (20.94 mmol, 7.85 g) was dissolved in acetonitrile (75 ml), 1 ,3-dimethyl-2-imidazolidinone (62.8 mmol, 6.9 ml, 7.17 g) was added and the reaction mixture was cooled to 0°C before POCI3 (84 mmol, 7.81 ml, 12.84 g) was added drop wise while the temperature remained around 5°C. The reaction mixture was refluxed at 60-65°C overnight. The reaction mixture was poured carefully in ammonium hydroxide 25% in water (250 ml)/crushed ice (500 ml) to give a yellow suspension (pH -8-9) which was stirred for 15 min until no ice was present in the suspension. Ethyl acetate was added, layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and evaporated to give 7.5 g crude product. The crude product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 6.6 g of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (88%).

(d) (S)-Benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The reaction was stirred 3 h at rt. The mixture was poored (slowly) in a stirred mixture of water (145 mL), ethyl acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and extracted. The water layer was extracted with 2×145 mL ethyl acetate. The combined organic layers were washed with 3×300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The product was purified using silica gel chromatography (ethyl acetate/heptane = 3/1 v/v%) to give 8.95 g of (S)-benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (82.3%).

(e) (S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (20.54 mmol, 8.95 g) was suspended in 2-propanol (1 13 ml) in a pressure vessel. 2-propanol (50 ml) was cooled to -78°C in a pre-weighed flask (with stopper and stirring bar) and ammonia gas (646 mmol, 1 1 g) was lead through for 15 minutes. The resulting solution was added to the suspension in the pressure vessel. The vessel was closed and stirred at room temperature and a slight increase in pressure was observed. Then the suspension was heated to 1 10 °C which resulted in an increased pressure to 4.5 bar. The clear solution was stirred at 1 10 °C, 4.5 bar overnight. After 18h the pressure remained 4 bar. The reaction mixture was concentrated in vacuum, the residue was suspended in ethyl acetate and subsequent washed with water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 7.35 g of (S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (86%).

Intermediate 2

Figure imgf000034_0001

(S)-4-(8-Amino-3-(pyrrolidin-2-v0im^

(a) (S)-Benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamov0

carboxylate

(S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (0.237 mmol, 98.5 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (0.260 mmol, 63.0 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (2.37 mmol, 1 .18 mL) and dioxane (2.96 mL). Nitrogen was bubbled through the mixture, followed by the addition of 1 , 1 ‘- bis(diphenylphosphino)ferrocene palladium (ii) chloride (0.059 mmol, 47.8 mg). The reaction mixture was heated for 20 minutes at 140°C in the microwave. Water was added to the reaction mixture, followed by an extraction with ethyl acetate (2x). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using silicagel and dichloromethane/methanol = 9/1 v/v% as eluent to afford 97.1 mg of (S)-benzyl 2-(8-amino-1-(4-(pyridin- 2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (77%).

(b) (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

To (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (0.146 mmol, 78 mg) was added a 33% hydrobromic acid/acetic acid solution (1 1.26 mmol, 2 ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide solution, and then extracted with dichloromethane. the organic layer was dried over magnesium sulfate, filtered and evaporated to give 34 mg of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide (58%).

Example 6

Figure imgf000038_0001

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

This compound was prepared, in an analogues manner as described in Example 2, from the compound described in intermediate 2b and 2-butynoic acid, to afford the title compound (10.5 mg, 18.0%). Data: LCMS (B) Rt : 2.08 min; m/z 466.1 (M+H)+.

PATENT

WO 2016024228

https://www.google.com/patents/WO2016024228A1?cl=en

PATENT

CN 107056786

Step SI:

[0029] The pressure in the reactor was added 3-chloro-2-carboxaldehyde l-yl P ratio of (II) (0.71g, 5mmol) and dioxane (20mL), under stirring ammonia gas (I. 7g, 0 . Imol), was added 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III) (2.42g, lOmmol), Ming dicarbonyl acetylacetonate (0.26g, lmmol), and water 4mL. The reactor was sealed, gradually warmed to 80~90 °, the reaction 16-18 hours, TLC detection, the reaction was complete. Concentrated under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and water successively, dried over anhydrous sodium sulfate. Concentrated to give brown oil, ethyl acetate and petroleum ether (volume ratio 1: 2) column chromatography to give an off-white solid 4- [amino (3-chloro-2-pyrazinyl) methyl] -N- (2-pyridyl) benzamide (IV) 1.38g, yield 81 · 2%; ESI-MS (m / z): 340 (m + H).

[0030] Step S2:

[0031] added in the reactor [1- (1-oxo-2-butyn-1-yl)] – L- proline (1.09g, 6mmol) and thionyl chloride (IOmL), was added dropwise 4mL of triethylamine and heated to 30 to 40 degrees, after the reaction for 2-4 hours under reduced pressure to remove excess thionyl chloride, the residue that is [I- (1- oxo-2-butyn-1-yl )] – L- proline acid chloride (V). The resulting [I- (1- oxo-2-butynyl -1_ yl)] _ L_ proline acid chloride (V) dissolved in 20mL dichloromethane burning, to a solution of 4- [amino (3-chloro -2-P ratio piperazinyl) methyl] -N- (2- pyridinyl) benzamide (IV) (1.35g, 4mmol) and triethylamine (0.6g, 6mmol) in dichloromethane (30mL) solution of in. Dropwise, warmed to 30-50 °, the reaction was stirred for 6 ~ 8 hours, TLC detection, the reaction was complete. Cooled to room temperature, washed with saturated sodium bicarbonate solution, brine and water, dried over anhydrous sodium sulfate. Concentrated to give a beige solid of 4- [1- (1-acyl-2-yne-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- (2- pyridinyl) benzamide (VI) 1.8g, yield 89.6% C3ESI-MS (m / z): 503 (m + H).

[0032] Step S3:

[0033] in a reaction flask was added 4- [I- (1- but-2-yn-acyl-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- ( 2-P ratio piperidinyl) benzamide (VI) (1 · 0g, 2mmol), phosphorus oxychloride (1 · 53g, IOmmol) and acetonitrile (25 mL), warmed to 80 ~ 100 ° with stirring, maintaining the temperature reaction 6 ~ 8 h, TLC the reaction was complete. Cooled to room temperature, the reaction solution was poured into 50mL concentration of 8% aqueous ammonia was added ethyl acetate, and the organic phase was separated, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and water, dried over anhydrous over sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid 4- [8-Chloro -3- [(2S) -I- (1- oxo-2 – butyn-1-yl) -2-pyrrolidinyl] imidazo [I, 5-a] pyrazin-1-yl] -N-2- pyridinyl benzamide (VII) 0.85g, yield 87.8 %; EI-MS m / z: 485 [m + H] + square

[0034] Step S4:

[0035] The pressure reactor was added to 4- [8-Chloro -3- [(2S) -I- (1- oxo-2-butyn-1-yl) -2-pyrrolidinyl] imidazo [ I, 5-a] pyrazin – Buji] -N-2- pyridinyl benzamide (VII) (0.48g, lmmol) and isopropanol (15 mL), cooled to 0 degrees, by controlling the dose into ammonia gas (0.51g, 30mmol), the reactor is closed, warmed up to room temperature for 1 hour, and then continuously increasing the reaction temperature to 110~120 °, maintained at the reaction temperature and pressure 20~24 h, TLC the reaction was complete. Cooled to room temperature, slowly vented, and concentrated under reduced pressure, the resulting residue was dissolved with ethyl acetate, water and saturated brine, dried over anhydrous sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid Acre imatinib ⑴ 0.40g, yield 86 · 0%; 1Η bandit R (DMS0-d6) 1.63 (m, lH), 1.97 (s, 3H), 2.02 ~2.12 (m, lH), 2 · 28~2.35 (m, 2H); 3.36~3.85 (m, 2H), 5 · 47~5.49 (m , lH), 6 · 17~6.23 (m, 2H), 7.12~7.20 (m, 2H), 7 · 73~7.86 (m, 4H), 8 · 16~8.25 (m, 3H), 8 · 41 ( dd, lH), 10.86 (s, lH); EI-MS m / z: 466 [m + H] +.

[0036] 3-chloro starting material employed in the method above relates to the present invention yl pyrazin-2-carbaldehyde (II) and 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III), respectively, refer to methods for their preparation Document “Tetrahedron Letters, 47 (l), 31-34; 2006” international Patent W02013010868 and method for preparing the same compound. Raw [1- (1-oxo-2-butyn-1-yl)] – L- proline acid chloride (V), in one embodiment, the compound may be made [the I-(1-oxo-known -2-yn-1-yl)] – L- proline acylation.

PATENT

US 20170224688

PATENT

CN 107522701

 Example I

[0030] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0031] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (10g, 28mmol) was dissolved in N- methylpyrrolidone ( SOML), the mass concentration was added 28% aqueous ammonia (168mm〇l), the reaction mixture was placed in a sealed stainless steel autoclave at 85 ° C, stirring the reaction under a pressure of 2.5 atm 6h, after the completion of the reaction, was cooled to 40 ° C and delivery system pressure, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin – 3- yl) -1-pyrrolidine-carboxylate, an off-white solid (8.5 g of), yield 90%, reaction formula of this step is as follows:

Figure CN107522701AD00091

[0033] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0034] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (8g, 24mmol) was dissolved in dichloromethane (IOOmL) was added tert-butyl dicarbonate (5.7g, 26mmol), reaction mixture was stirred 3h at 25 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (IoG), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00092

[0036] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0037] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (IOg, 23mmol) was dissolved in tetrahydrofuran ( 80mL), was slowly added N- bromosuccinimide (4.5g, 25mmol), the reaction mixture was 25 ° C the reaction was stirred for 4h. The mixture was then slowly added water (80 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (I I. Ig), a yield of 94.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00093

[0039] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0040] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (I Ig, 2lmmol ), 4- (2-pyridyl-carbamoyl) phenylboronic acid (5.7g, 23.4mmol), [1, Γ – bis (diphenylphosphino) ferrocene] dichloropalladium cesium (〇.78g, the I · lmmol), potassium carbonate (4.0g, 29mmol), N, N- dimethylformamide (120 mL) and water (50mL) added to the reaction flask, the reaction mixture was heated to 90 ° C the reaction was stirred for 20 h, the reaction solution was reduced at room temperature, was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give (S) -2- {8- tert butoxycarbonyl group -I- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, class as a white solid (10.3 g of), a yield of 76.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00101

[0042] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0043] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- [1-carboxylic acid than the burning section slightly ester (10g, 15.8mmol) was dissolved in methanol (80mL), was added cesium charcoal (0.5g), under a hydrogen pressure into 35 ° C the reaction 8h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (7.6 g of), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00102

[0045] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0046] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (7g, 14mmol) was dissolved in tetrahydrofuran (75 mL), with stirring, was added 2-butyne chloride (I. 7g, 16.6mmol), was added dropwise N, N- diisopropylethylamine (2.7 g, 21 mmol), the reaction mixture was 50 ° C the reaction was stirred for 8h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give ⑸ -2_ {8-tert-butoxycarbonyl-amino -1- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] [! than 3-yl} -1 – (2_ butynoyl) pyrrolidine-white solid (7g), in 88% yield, this step follows the reaction formula:

Figure CN107522701AD00111

[0048] ⑺ prepared Acalabrutinib:

[0049] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (7g, 12.4mmol) and dissolved in methanol (70 mL), trifluoroacetic acid (1.55g, 13.6mmol), 65 ° C until the reaction was complete the reaction was stirred for 6h, the reaction was added dropwise to a stirred solution of water (150 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors Acalabrut inib, as a white solid (5.3 g of), 92% yield, this step is the following reaction formula:

Figure CN107522701AD00112

[0051] Example 2:

[0052] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0053] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 42mmol) was dissolved in N- methylpyrrolidone ( 75 mL), aqueous ammonia (273_〇1) was added mass percent concentration of 28%, the reaction mixture was placed in a sealed stainless steel autoclave at 70 ° C, stirring the reaction under a pressure of 3 atm 8h, after the completion of the reaction, was cooled to 40 ° C and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (12.9 g of), yield 91% ,, this step reaction scheme in Example 1.

[0054] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0055] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (12g, 35.6mmol) was dissolved in chloroform (80mL), was added tert-butyl dicarbonate (7.8g, 35.6mmol), the reaction mixture was stirred for lh the reaction at 35 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (14.8 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0056] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0057] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (Hg, 32mmol) was dissolved in 1, 1,2-dichloroethane (90mL), was slowly added bromine (6g, 37.8mmol), the reaction mixture was 20 ° C the reaction was stirred for 6h. After the reaction, water was slowly added (I5mL), cooled to -5 ° C crystallization 4h, filtered and recrystallized from isopropanol to give ⑸-2- (8- tert-butoxycarbonyl-amino-1-bromo-imidazo [1, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (15.8 g), yield 95.5%, the reaction of the present step is the same formula as in Example 1.

[0058] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0059] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 29mmol) , 4- (2-pyridyl-carbamoyl) phenylboronic acid (34 · 7mmol 8 · 4g,), tetrakis (triphenylphosphine) palladium (0 · 84g, 0.73mmol), sodium carbonate (6.9g, 65mmol), tetrahydrofuran (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 80 ° C the reaction was stirred for 24h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazole and [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (14.4g), 78% yield, this step is the same reaction scheme as in Example 1.

[0060] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0061] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3- it is slightly burned} -1-carboxylic acid ester section (14g, 22mmol) dissolved in isopropanol (85mL), was added Raney nickel (0.5g), under a hydrogen pressure into the reaction 60 ° C 12h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (10.4 g of), 94% yield, this step is the same reaction scheme as in Example 1.

[0062] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0063] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } pyrrolidine (10g, 20mmo 1) was dissolved in N, N- dimethylformamide (SOML), with stirring, was added 2-butyne chloride (3. lg, 30mmol), dropwise addition of triethylamine (2.2g, 22mmol ), the reaction mixture was 60 ° C the reaction was stirred for 4h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸- 2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -l- (2- butynoyl) pyrrolidine-white solid (10.2 g of), a yield of 90.2%, the same reaction scheme of the present embodiment step 1〇

[0064] ⑺ prepared Acalabrutinib:

[0065] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (IOg, 17.7mmol) was dissolved in ethanol, and (IOOmL), trifluoroacetic acid (2.6g, 23mmol), 50 ° C with stirring until the reaction was complete IOh reaction, the reaction solution was added dropwise to a stirred solution of water (70 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (7.5 g of), yield 91%, reaction of this step formula same as in Example 1.

[0066] Example 3:

[0067] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0068] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4.5g, 12.6mmol) was dissolved in N- methyl pyrrolidinone (70 mL), was added mass percent concentration of 28% aqueous ammonia (69.4 mmol), the reaction mixture was placed in the autoclave 90 ° C, the reaction was stirred under atmospheric pressure of 4h, after the completion of the reaction, it was cooled to 35 ° C a sealed stainless steel reactor and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (3.9 g of), 92% yield, this step is the same reaction scheme as in Example 1.

[0069] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0070] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester (3 · 5g, 10 · 4mmol) was dissolved in 1, 4- dioxane (50 mL), was added tert-butyl dicarbonate (2.7g, 12.4mmol), the reaction mixture was stirred at 10 ° C the reaction 6h, after the completion of the reaction, workup and purification, to give (S) 2- (8-tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.3 g of), in 95% yield, according to the present step reaction scheme in Example 1.

[0071] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0072] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [l, 5_a] pyrazin-3-yl) -1_ pyrrolidine-carboxylate (4g, 9.6mmol) was dissolved in toluene (50 mL ), was slowly added N- bromosuccinimide (I. 8g, 10. lmmol), the reaction mixture was 35 ° C the reaction was stirred for 2h. The mixture was then slowly added water (25 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.7 g), 94% yield, this step is the same reaction scheme as in Example 1.

[0073] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0074] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4g, 7 · 7mmol), 4_ (2- piperidinyl than Jie carbamoyl) phenylboronic acid (2 · 4g, IOmmol), bis (triphenylphosphine) dichloride Leba (0.41g, 0.58mmol), potassium phosphate (I. 9g, 8.9mmol), methyl tert-butyl ether (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 100 ° C the reaction was stirred for 12h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, was added acetic acid extracted with ethyl, brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2 – pyridin-ylcarbamoyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (3.9 g of), in 79% yield, this step the reaction scheme in Example 1.

[0075] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5_a] pyrazin-3 -} pyrrolidine:

[0076] (S) -2- {8- tert-butoxycarbonyl group -I- [4- (2- carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1 Jie section than slightly burning acid ester (3.5g, 5.5mmol) was dissolved in ethanol (50mL), was added cesium charcoal (0.2g), under a hydrogen pressure into 45 ° C the reaction 6h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (2.6 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0077] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0078] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (2.5g, 5mmol) was dissolved in toluene (50 mL), with stirring, was added 2-butyne chloride (0.62g, 6mmol), was added dropwise N, N- dimethylaniline (Ig, 8.5mmo 1), The reaction mixture was 40 ° C the reaction was stirred for 12h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸-2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1- (2-butyn acyl) pyrrolidine-white solid (2.5g), 88% yield, this step is the same reaction scheme as in Example 1.

[0079] ⑺ prepared Acalabrutinib:

[0080] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3_ } -1- (2-block group) ratio slightly burning Jie (2.5g, 4.4mmol) was dissolved in dichloromethane and burned (IOmL), two gas was added acetic acid (0.76g, 6.6mmol), 80 ° C The reaction was stirred 4h until the reaction was complete, the reaction was added dropwise to a stirred solution of water (25 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (1.8 g of), the yield of 89%, this step is the same reaction scheme as in Example 1.

PATENT

US 20170035881

References

  1. Jump up^ “WHO Drug Information – recommended INN” (PDF). WHO Drug Information. World Health Oorganisation. Retrieved 24 December 2015.
  2. Jump up to:a b c d Byrd; et al. (2015). “Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia”doi:10.1056/NEJMoa1509981.
  3. Jump up to:a b c d e f g h i Wu, Jingjing; Zhang, Mingzhi; Liu, Delong (2016-01-01). “Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor”Journal of Hematology & Oncology9: 21. doi:10.1186/s13045-016-0250-9ISSN 1756-8722PMC 4784459Freely accessiblePMID 26957112.
  4. Jump up^ “AstraZeneca to buy Acerta for blood cancer drug”http://www.rsc.org. Chemistry World – Royal Society of Chemistry. Retrieved 24 December 2015.
  5. Jump up^ Wu, Jingjing; Zhang, Mingzhi; Liu, Delong (2016-03-09). “Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor”Journal of Hematology & Oncology9 (1). doi:10.1186/s13045-016-0250-9ISSN 1756-8722PMC 4784459Freely accessiblePMID 26957112.
  6. Jump up to:a b c Harrington, Bonnie K.; Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael (2016-07-19). “Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma”PLOS ONE11 (7): e0159607. doi:10.1371/journal.pone.0159607ISSN 1932-6203PMC 4951150Freely accessiblePMID 27434128.
  7. Jump up to:a b Acerta Pharma Announces Study Published in New England Journal of Medicine Demonstrates Acalabrutinib (ACP-196) Shows Marked Activity in Relapsed Chronic Lymphocytic Leukemia
  8. Jump up^ 21 studies found for: ACP-196
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  12. Jump up^ House, SA Editor Douglas W. (2016-02-25). “AstraZeneca and Acerta Pharma’s acalabrutinib tagged an Orphan Drug in Europe for three indications”Seeking Alpha. Retrieved 2016-11-21.
  13. Jump up^ “Acerta Pharma B.V. – Company Profile – BioCentury”http://www.biocentury.com. Retrieved 2016-11-12.
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  16. Jump up^ Walker, Ian; Roland, Denise (2015-12-17). “AstraZeneca to Buy Stake in Acerta Pharma”Wall Street JournalISSN 0099-9660. Retrieved 2016-11-19.
  17. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Nov 26, 2015), Btk inhibitor for the treatment of chronic lymphocytic and small lymphocytic leukemia, retrieved 2016-11-19
  18. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Jun 11, 2015), Therapeutic combination of a pi3k inhibitor and a btk inhibitor, retrieved 2016-11-19
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ADDITIONAL INFORMATION

Acalabrutinib is a potent and selective BTK (Bruton’s tyrosine kinase) inhibitor. BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. BTK inhibitors targeting B cell receptor signaling and other survival mechanism showed great promise for the treatment of chronic lymphocytic leukemia (CLL)s holds great promise.

As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.

REFERENCES

1: Maly J, Blachly JS. Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents. Curr Hematol Malig Rep. 2016 Feb 11. [Epub ahead of print] PubMed PMID: 26893063.

2: Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7. PubMed PMID: 26641137.

Patent ID

Patent Title

Submitted Date

Granted Date

US2017231995 BTK Inhibitors to Treat Solid Tumors Through Modulation of the Tumor Microenvironment
2015-08-11
US2017095471 Methods of Treating Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Using a BTK Inhibitor
2015-01-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2017231986 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
2015-08-11
US2017035756 METHODS OF BLOCKING THE CXCR-4/SDF-1 SIGNALING PATHWAY WITH INHIBITORS OF BRUTON’S TYROSINE KINASE
2015-04-10
US2017266191 Therapeutic Combination of PI3K Inhibitor and a BTK Inhibitor
2014-12-05
US2016159810 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-09
US2017143712 Methods of Treating Cancers, Immune and Autoimmune Diseases, and Inflammatory Diseases Based on BTK Occupancy and BTK Resynthesis Rate
2017-02-07
Patent ID

Patent Title

Submitted Date

Granted Date

US2017035881 Therapeutic Combinations of an IRAK4 Inhibitor and a BTK Inhibitor
2016-10-19
US2017071962 Therapeutic Combinations of a Proteasome Inhibitor and a BTK Inhibitor
2016-09-12
US9717745 PHARMACEUTICAL COMPOSITIONS AND THEIR USE FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASES
2016-06-15
US9758524 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-02
US2017224819 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a CDK 4/6 Inhibitor
2015-08-11
Patent ID

Patent Title

Submitted Date

Granted Date

US2017029428 Solid Forms and Formulations of Imidazopyrazine Compound
2016-07-01
US2017239351 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, a PD-1 Inhibitor, and/or a PD-L1 Inhibitor
2015-08-11
US2017136014 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor and/or a JAK-2 Inhibitor
2015-06-17
US9290504 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2012-07-11
2014-06-05
US2017224688 Methods of Using BTK Inhibitors to Treat Dermatoses
2017-02-03
Acalabrutinib
Acalabrutinib.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C26H23N7O2
Molar mass 465.507 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 9290504
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent 9758524
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent 9796721
Expiration Jul 1, 2036
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)

////////////AcalabrutinibrINNACP-196, fda 2017, Акалабрутиниб , أكالابروتينيب , 阿可替尼 , Orphan Drug, breakthrough therapy designation, Lymphoma, mantle cell, ACERTA PHARMA

CC#CC(=O)N1CCC[C@H]1c2nc(c3n2ccnc3N)c4ccc(cc4)C(=O)Nc5ccccn5

CC#CC(=O)N1CCCC1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5

FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Hemlibra 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 Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves new treatment for certain advanced or metastatic breast cancers


FDA approves new treatment for certain advanced or metastatic breast cancers

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized). Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm

Abemaciclib.svg

(abemaciclib)

September 28, 2017

Release

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized).

“Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and 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.

Verzenio works by blocking certain molecules (known as cyclin-dependent kinases 4 and 6), involved in promoting the growth of cancer cells. There are two other drugs in this class that are approved for certain patients with breast cancer, palbociclib approved in February 2015 and ribociclib approved in March 2017.

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The safety and efficacy of Verzenio in combination with fulvestrant were studied in a randomized trial of 669 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and who had not received chemotherapy once the cancer had metastasized. The study measured the length of time tumors did not grow after treatment (progression-free survival). The median progression-free survival for patients taking Verzenio with fulvestrant was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant.

The safety and efficacy of Verzenio as a stand-alone treatment were studied in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. The study measured the percent of patients whose tumors completely or partially shrank after treatment (objective response rate). In the study, 19.7 percent of patients taking Verzenio experienced complete or partial shrinkage of their tumors for a median 8.6 months.

Common side effects of Verzenio include diarrhea, low levels of certain white blood cells (neutropenia and leukopenia), nausea, abdominal pain, infections, fatigue, low levels of red blood cells (anemia), decreased appetite, vomiting and headache.

Serious side effects of Verzenio include diarrhea, neutropenia, elevated liver blood tests and blood clots (deep venous thrombosis/pulmonary embolism). Women who are pregnant should not take Verzenio because it may cause harm to a developing fetus.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted the approval of Verzenio to Eli Lilly and Company.

//////////Verzenio, abemaciclib, fda 2017, metastatic breast cancers, Eli Lilly ,  Priority Review,  Breakthrough Therapy designations, antibodies

FDA approval brings first gene therapy to the United States


Image result for FDA approval brings first gene therapy to the United States
08/30/2017
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases

The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.

The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.

Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

/////////////Kymriah, Novartis Pharmaceuticals Corp, Actemra, Genentech Inc., gene therapy, fda 2017

FDA approves Vosevi for Hepatitis C


07/18/2017
The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////////Vosevi, Gilead Sciences Inc, Priority Review, Breakthrough Therapy designations, fda 2017, sofosbuvir,  velpatasvir , voxilaprevir, Hepatitis B

FDA approves first drug Actemra (tocilizumab) to specifically treat giant cell arteritis


Image result for actemra logo
05/22/2017
The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

May 22, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

“We expedited the development and review of this application because this drug fulfills a critical need for patients with this serious disease who had limited treatment options,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels. This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries (located on each side of the head). For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

The efficacy and safety of subcutaneous (injected under the skin) Actemra for giant cell arteritis were established in a double-blind, placebo-controlled study with 251 patients with giant cell arteritis. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone (a steroid drug). A greater proportion of patients receiving subcutaneous Actemra with standardized prednisone regimens achieved sustained remission from Week 12 through Week 52 as compared to patients receiving placebo with standardized prednisone regimens. The cumulative prednisone dose was lower in treated patients with Actemra relative to placebo.

The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. Actemra carries a Boxed Warning for serious infections. Patients treated with Actemra who develop a serious infection should stop that treatment until the infection is controlled. Live vaccines should be avoided during treatment with Actemra. Actemra should be used with caution in patients at increased risk of gastrointestinal perforation. Hypersensitivity reactions, including anaphylaxis and death, have occurred. Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils (type of white blood cell), platelets, lipids and liver function tests.

Subcutaneous Actemra was previously approved for the treatment of moderate to severely active rheumatoid arthritis. Intravenous Actemra was also previously approved for the treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. Intravenous administration is not approved for giant cell arteritis.

The FDA granted this application a Breakthrough Therapy designation and a Priority Review.

The FDA granted the supplemental approval of Actemra to Hoffman La Roche, Inc.

//////////Actemra, tocilizumab, fda 2017, Breakthrough Therapy designation, Priority Review,  supplemental approval, Hoffman La Roche, Inc.

FDA approves first treatment for a form of Batten disease, Brineura (cerliponase alfa)


Image result
04/27/2017
The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

“The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition.”

CLN2 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease. CLN2 disease is a rare inherited disorder that primarily affects the nervous system. In the late infantile form of the disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.

Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

The efficacy of Brineura was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.

The safety of Brineura was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura in clinical studies. The safety and effectiveness of Brineura have not been established in patients less than 3 years of age.

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure.

Brineura should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).

Health care providers should also monitor vital signs (blood pressure, heart rate, etc.) before the infusion starts, periodically during infusion and post-infusion in a health care setting. Health care providers should perform electrocardiogram (ECG) monitoring during infusion in patients with a history of slow heart rate (bradycardia), conduction disorder (impaired progression of electrical impulses through the heart) or structural heart disease (defect or abnormality of the heart), as some patients with CLN2 disease can develop conduction disorders or heart disease. Hypersensitivity reactions have also been reported in Brineura-treated patients. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated.

The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years.

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

The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucherunder a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.

////////Brineura, cerliponase alfa, fda 2017, Batten disease, BioMarin Pharmaceutical Inc, Priority Review,  Breakthrough Therapy designations, Orphan Drug designation,

FDA approves first drug Ingrezza (valbenazine) to treat tardive dyskinesia


Valbenazine.svg

Valbenazine

  • Molecular FormulaC24H38N2O4
  • Average mass418.569 Da
(2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl L-valinate
(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl L-valinate
1025504-45-3 cas
L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester
NBI-98854
Image result for valbenazine
Valbenazine ditosylate. RN: 1639208-54-0. UNII: 5SML1T733B, Molecular Formula, C24-H38-N2-O4.2C7-H8-O3-S, Molecular Weight, 762.9806

(2R,3R,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-yl L-valinate bis(4-methylbenzenesulfonate)

and

Valbenazine dihydrochloride
1639208-51-7

04/11/2017
The U.S. Food and Drug Administration today approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.

April 11, 2017

Release

The U.S. Food and Drug Administration today approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.

Tardive dyskinesia is a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips and tongue, such as grimacing, sticking out the tongue and smacking the lips. Some affected people also experience involuntary movement of the extremities or difficulty breathing.

“Tardive dyskinesia can be disabling and can further stigmatize patients with mental illness,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of tardive dyskinesia is an important advance for patients suffering with this condition.”

Tardive dyskinesia is a serious side effect sometimes seen in patients who have been treated with antipsychotic medications, especially the older medications, for long periods to treat chronic conditions, such as schizophrenia and bipolar disorder. Tardive dyskinesia can also occur in patients taking antipsychotic medications for depression and certain medications for gastrointestinal disorders and other conditions. It is unclear why some people who take these medications develop tardive dyskinesia yet others do not.

The efficacy of Ingrezza was shown in a clinical trial of 234 participants that compared Ingrezza to placebo. After six weeks, participants who received Ingrezza had improvement in the severity of abnormal involuntary movements compared to those who received placebo.

Ingrezza may cause serious side effects including sleepiness and heart rhythm problems (QT prolongation). Its use should be avoided in patients with congenital long QT syndrome or with abnormal heartbeats associated with a prolonged QT interval. Those taking Ingrezza should not drive or operate heavy machinery or do other dangerous activities until it is known how the drug affects them.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations.

The FDA granted approval of Ingrezza to Neurocrine Biosciences, Inc.

Valbenazine (INN,[1]:114 proposed trade name Ingrezza) is the first drug approved by the FDA[2] for use in the treatment of tardive dyskinesia.[3][4] Clinical trials are underway to evaluate its efficacy in the treatment of Tourette’s syndrome.[5][6] It acts as a vesicular monoamine transporter 2 (VMAT2) inhibitor.[7]

Pharmacology

Mechanism of action

Valbenazine is known to cause reversible reduction of dopamine release by selectively inhibiting pre-synaptic human vesicular monoamine transporter type 2 (VMAT2). In vitro, valbenazine shows great selectivity for VMAT2 and little to no affinity for VMAT1 or other monoamine receptors.[8] Although the exact cause of tardive dyskinsia is unknown, it is hypothesized that it may result from neuroleptic-induced dopamine hypersensitivity.[9] By selectively reducing the ability of VMAT2 to load dopamine into synaptic vesicles,[10] the drug reduces overall levels of available dopamine in the synaptic cleft, ideally alleviating the symptoms associated with dopamine hypersensitivity. The importance of valbenazine selectivity inhibiting VMAT2 over other monoamine transporters is that VMAT2 is mainly involved with the transport of dopamine, and to a much lesser extent other monoamines such as norepinephrine, serotonin, and histamine. This selectivity is likely to reduce the likelihood of “off-target” adverse effects which may result from the upstream inhibition of these other monoamines.[11]

Society and culture

Commercial aspects

Valbenazine is produced by Neurocrine Biosciences, a company based in San Diego. In addition to the late-stage clinical trials studying valbenazine, Neurocrine Biosciences (partnered with AbbVie Inc.) also has another product, elagolix (a hormone antagonist), undergoing clinical trials.[12] Following the initiation of these trials, on 5 May 2016 Neurocrine reported revenues of $15 million for the first quarter of 2016.[13] The company now focuses on filing the valbenazine new drug application as they prepare for the commercial launch of the drug for the treatment of tardive dyskinesia.Neurocrine’s expenses have risen steadily since May 2015, primarily due to the pre-commercialization activities for valbenazine. [14]

Intellectual property

While Neurocrine Biosciences does not currently hold a final patent for valbenazine or elagolix, they do hold a patent for the VMAT2 inhibitor [9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido-[2,1-a]isoquinolin-2-yl]methanol and related compounds, which includes valbenazine.[15]

ChemSpider 2D Image | Valbenazine | C24H38N2O4

References

  1.  “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 71” (PDF). World Health Organization. Retrieved 18 November 2016.
  2.  Newswire, MultiVu – PR. “Neurocrine Announces FDA Approval of INGREZZA TM (valbenazine) Capsules as the First and Only Approved Treatment for Adults with Tardive Dyskinesia (TD)”. Multivu. Retrieved 2017-04-11.
  3.  Ben Adams (Aug 30, 2016). “Neurocrine submits valbenazine NDA early, set for 2017 approval”. fiercebiotech.com.
  4.  “Safety and Tolerability Study of NBI-98854 for the Treatment of Tardive Dyskinesia – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2016-11-13.
  5. Jump up^ “Tourette Syndrome Clinical Trials | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-13.
  6. Jump up^ “Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2016-11-13.
  7. Jump up^ O’Brien, C. F.; Jimenez, R; Hauser, R. A.; Factor, S. A.; Burke, J; Mandri, D; Castro-Gayol, J. C. (2015). “NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study”. Movement Disorders. 30 (12): 1681–7. doi:10.1002/mds.26330. PMC 5049616Freely accessible. PMID 26346941.
  8. Jump up^ “NBI-98854 – VMAT2 Inhibitor | Tics in Children Treatment | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-13.
  9. Jump up^ “tardive-dyskinesia”. http://www.priory.com. Retrieved 2016-11-13.
  10. Jump up^ Purves, Dale, et al. Neuroscience. Sinauer Associates. 087893646
  11.  “NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…”. Retrieved 2016-11-13.
  12.  “Endocrine & Movement Disorder R&D | About | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-14.
  13.  “NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…”. Retrieved 2016-11-20.
  14.  “Press Release | Neurocrine Biosciences, Inc.”. phoenix.corporate-ir.net. Retrieved 2016-11-20.
  15.  “[9,10-dimethoxy-3-(2-methylpropyl)-1h,2h,3h,4h,6h,7h,11bh-pyrido-[2,1-a]isoquinolin-2-yl]methanol And Compounds, Compositions And Methods Relating Thereto”. Retrieved 2016-11-20.
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Patent ID Patent Title Submitted Date Granted Date
US8039627 SUBSTITUTED 3-ISOBUTYL-9, 10-DIMETHOXY-1, 3, 4, 6, 7, 11B-HEXAHYDRO-2H-PYRIDO[2, 1-A]ISOQUINOLIN-2-OL COMPOUNDS AND METHODS RELATING THERETO 2008-07-10 2011-10-18
US8357697 Substituted 3-isobutyl-9, 10-dimethoxy-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrido[2, 1-A]isoquinolin-2-ol compounds and methods relating thereto 2011-09-20 2013-01-22
US2016068526 BENZOQUINOLONE INHIBITORS OF VMAT2 2014-01-28 2016-03-10
Valbenazine
Valbenazine.svgImage result for valbenazine
Clinical data
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
Synonyms NBI-98854
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C24H38N2O4
Molar mass 418.58 g·mol−1
3D model (Jmol)
////////fda 2017, Ingrezza, valbenazine, tardive dyskinesia, Fast Track, Priority Review ,  Breakthrough Therapy designations, 1025504-45-3, NBI-98854, 
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