New Drug Approvals

Home » Posts tagged 'fda' (Page 27)

Tag Archives: fda

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 4,823,557 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 37.9K other subscribers
Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

SUBSCRIBE

New Drug Approvals

↑ Grab this Headline Animator

Subscribe in a reader

Enter your email address:

Delivered by FeedBurner

Subscribe to New Drug Approvals by Email

Add to Google Reader or Homepage

Subscribe in Bloglines

Add to The Free Dictionary

I heart FeedBurner

Subscribe in NewsGator Online

Add to netvibes

Add to Excite MIX

Add to fwicki

Add to Webwag

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 37.9K other subscribers
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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Phase 2 Drug: Ustekinumab A monoclonal antibody against the p40 subunit of IL-12/23 Other Name: Stelara

March 11, 2013 12:54 am / 4 Comments on Phase 2 Drug: Ustekinumab A monoclonal antibody against the p40 subunit of IL-12/23 Other Name: Stelara


Monoclonal antibody
Type Whole antibody
Source Human
Target IL-12 and IL-23

 

Ustekinumab CAS# 815610-63-0

Ustekinumab, CAS number 815610-63-0, is also known by it’s brand name Stelara, which is marketed by Janssen Biotech, Inc. Developed as a treatment for adults with moderate to severe plaque psoriasis

 

Rockefeller University, MAR 2013

http://clinicaltrials.gov/ct2/show/NCT01806662

Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects most aspects of everyday life in the majority of patients. Acute inflammation and extensor/facial involvement is common in infants, whereas chronic inflammation increases in prevalence with age, as do localization to flexures. AD has a complex background characterized by immune activation, increased epidermal thickness in chronic diseased skin, and defective barrier function. In normal, healthy skin, the outer layer of the epidermis, the stratum corneum is made up flattened dead cells called corneocytes held together by a mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are vital in providing a natural barrier function that locks water inside the skin and keeps allergens and irritants out. In people with AD, the barrier function is defective, which leads to dry skin. As the skin dries out, it cracks allowing allergens and irritants to penetrate.

Mild AD can be controlled with emollients and topical medications. However, moderate to severe AD is extremely difficult to control and requires systemic treatment that is often unsatisfactory due to impracticality and lack of effectiveness. Only three therapeutic options exist for moderate to severe AD, including: 1) oral steroids 2) cyclosporine A (CsA), that is not widely used in the US as it is not FDA approved for AD and 3) ultraviolet phototherapy. Oral steroids and CsA treatments have major side effects and UV radiation therapy is highly inconvenient for patients. Several biologic medications, such as TNF-alpha inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may specifically target AD.

The investigators study will determine whether there is a reversal of the skin thickness and the immune pathways involved in the disease during treatment with Ustekinimab and what specific immune cells are involved. The investigators are also interested to understand how the clinical reversal of the disease will correlate with tissue reversal of the disease.
Detailed Description:

In psoriasis, epidermal hyperplasia is driven by underlying immune activation, whether as a direct response to IL-20 family cytokines that induces hyperplasia and inhibits keratinocyte terminal differentiation or as an indirect response to immune-mediated injury to keratinocytes. The epidermal reaction in psoriasis is largely restored to normal with selective immune suppression. Hence, one might hypothesize that similar epidermal responses should occur in the presence of “generalized” cellular immune activation, in diseases with similar inflammatory infiltrate and epidermal hyperplasia, such as AD. In fact, psoriasis and AD share features of dense T-cells and dentritic cell infiltrates, as well as over-expression of IL-22 in skin lesions. These diseases also share similar epidermal hyperplasia in their chronic phases.

Work from the investigators group showed that IL-22 is a key cytokine in the pathogenesis of both AD and psoriasis. The investigators have demonstrated that in psoriasis, ustekinumab suppresses the production of IL-12, IL-23, and IL-22. Additionally, by RT-PCR the investigators demonstrated that the mRNA expression of p40 cytokine and the IL23R is up-regulated in AD as compared to both normal skin and psoriasis. The investigators therefore hypothesize that ustekinumab will suppress IL-22 and possibly also p40 production in AD lesions and reverse both the epidermal growth/differentiation defects and the underlying immune activation, and hence will suppress disease activity. Interestingly, p40 was also found to be significantly up-regulated in non-lesional AD skin as compared with normal skin.

Although AD is thought to be predominately a disease of Th2-type cells, in the chronic stage, there is large Th1 component. To date, the precise mechanism by which sequential activation of Th2 and Th1 cells in AD is achieved remains unknown. IL-12 induces the differentiation and maturation of human Th cells into Th1-type cells. Recent circumstantial evidence suggests that in AD patients IL-12 may facilitate a change from the Th2-type to a Th1 cytokine profile. IL-12 was recently shown to be highly elevated in pediatric AD and its levels were strongly associated with disease severity.

Expression of IL-12 p40 mRNA is significantly enhanced in lesional skin from AD, suggesting that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for the increased production of IFN-γ in chronic lesions potentially suggesting that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis. Topical steroids which constitute a mainstay of therapy in AD are known to strongly down-regulate IL-12 expression, possibly also indicating that targeted anti IL-12 therapy might important role in treating AD.

Recently, the Th1/Th2 paradigm in autoimmunity and allergy has been revisited to include a role for a new population of IL-17-producing Th cells known as Th17. Th17 cells are characterized by the production of inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-26. One of the key factors involved in naive Th-cell commitment to a Th17 phenotype is IL-23.

Patients with acute AD were found to have increased Th17 T-cells in peripheral blood by flow cytometry and intracellular cytokine staining 26 as well as by immunohistochemistry (IHC) in lesions. Since IL-23 is the major inducer of Th17 T-cells, as well as “T22” T-cells, neutralization of IL-23 could potentially result in both decreased Th17 signal in acute AD as well as decreased “T22/IL22″ signal. Therefore the investigators postulate that ustekinumab in AD will act both inhibiting the IL-12-dependent Th1 shift in chronic AD stage as well as the pathogenic IL-22/”T22” axis in this disease.

Ustekinumab [1] (INN, experimental name CNTO 1275, proprietary commercial name Stelara,[2] Centocor) is a human monoclonal antibody. It is directed against interleukin 12 and interleukin 23, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.[3]

In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.[4][5]

A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis.[6] This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept.[6] It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.[6]

Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.[7]

As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis.[8][9] It has also been tested in Phase II studies for multiple sclerosis[10] and sarcoidosis, the latter versus golimumab (Simponi).[11]

  1. Cingoz, Oya (2009). “Ustekinumab”. MAbs 1 (3): 216–221. doi:10.4161/mabs.1.3.8593. PMC 2726595. PMID 20069753.
  2. ^ European Medicines Agency, 20 November 2008, http://www.emea.europa.eu/pdfs/human/opinion/Stelara_58227008en.pdf
  3. ^ Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U (May 2007). “Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275”. Cell. Immunol. 247 (1): 1–11. doi:10.1016/j.cellimm.2007.06.006. PMID 17761156.
  4. ^ Leonardi CL, Kimball AB, Papp KA, et al. (May 2008). “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)”. Lancet 371 (9625): 1665–74. doi:10.1016/S0140-6736(08)60725-4. PMID 18486739.
  5. ^ Papp KA, Langley RG, Lebwohl M, et al. (May 2008). “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)”. Lancet 371 (9625): 1675–84. doi:10.1016/S0140-6736(08)60726-6. PMID 18486740.
  6. ^ a b c Griffiths C, Strober B, van de Kerkhof P et al. (2010). “Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis”. N Engl J Med 362 (2): 118–28. doi:10.1056/NEJMoa0810652. PMID 20071701.
  7. ^ Medarex to Receive Milestone Payment for Approval of STELARA(TM) (Ustekinumab) for the Treatment of Moderate to Severe Plaque Psoriasis
  8. ^ ClinicalTrials.gov NCT00267956 A Study of the Safety and Efficacy of CNTO 1275 in Patients With Active Psoriatic Arthritis
  9. ^ ClinicalTrials.gov NCT01009086 A Study of the Safety and Efficacy of Ustekinumab in Patients With Psoriatic Arthritis
  10. ^ ClinicalTrials.gov NCT00207727 A Safety and Efficacy Study of CNTO1275 in Patients With Multiple Sclerosis
  11. ^ ClinicalTrials.gov NCT00955279 A Study to Evaluate the Safety and Effectiveness of Ustekinumab or Golimumab Administered Subcutaneously (SC) in Patients With Sarcoidosis
  12. ^ http://www.empr.com/stelara-approved-for-moderate-to-severe-psoriasis/article/149760/
  13. ^ a b Centocor 12/19/08 Press Release, http://www.centocor.com/centocor/i/press_releases/FDA_ISSUES_COMPLETE_RESPONSE_LETTER_TO_CENTOCOR_FOR_USTEKINUMAB_BIOLOGIC_LICENSE_APPLICATION_
  14. ^ Johnson LL. “Study: Drug for serious psoriasis tops competition” The Associated Press. 18 Sept 2008.[dead link]
  15. ^ Wild, David (November 2011), “Novel IL-12/23 Antagonist Shows Potential in Severe Crohn’s”, Gastroenterology & Endoscopy News 62 (11), retrieved 2011-12-04
  16. ^ a b c Weber J, Keam SJ (2009). “Ustekinumab”. BioDrugs 23 (1): 53–61. doi:10.2165/00063030-200923010-00006. PMID 19344192.
  17. ^ Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH (September 2008). “Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study”. Lancet Neurol 7 (9): 796–804. doi:10.1016/S1474-4422(08)70173-X. PMID 18703004.
  18. ^ “Important Safety Information”. STELARA® (ustekinumab). Janssen Biotech.

External links

10 MAR 2013, MAA EU SUBMITTED, APPROVED US, CANADA, LURASIDONE, LATUDA, SCHIZOPRENIA, DAINIPPON SUMITOMO

March 10, 2013 5:24 am / 4 Comments on 10 MAR 2013, MAA EU SUBMITTED, APPROVED US, CANADA, LURASIDONE, LATUDA, SCHIZOPRENIA, DAINIPPON SUMITOMO


LURASIDONE

(3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione

STATUS AS ON 10 MARCH 2012

Lurasidone (trade name Latuda) is an atypical antipsychotic developed by Dainippon Sumitomo Pharma.[1] It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia on October 28, 2010[2] after a review that found that two of the four Phase III clinical trials supported efficacy, while one showed only marginal efficacy and one was not interpretable because of high drop-out rates.[3] It is currently pending approval for the treatment of bipolar disorder in the United States.

Clinical effects

In clinical studies, lurasidone alleviates positive symptoms (e.g., hallucinations, delusions) without inducing extrapyramidal side effects except for akathisia,[4] despite its potent D2 antagonistic actions. Effectiveness against negative symptoms of schizophrenia has yet to be established.

Lurasidone may be useful for treating the cognitive and memory deficits seen in schizophrenia. In animal studies, it reversed dizocilpine-induced learning and memory impairment and was found to be superior in doing this to all of the other antipsychotics examined, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.[5][6] Lurasidone has activity at several serotonin receptors that are involved in learning and memory, and unlike most other antipsychotics, lacks any anticholinergic effects (which are known to impair cognitive processes and memory).[5] These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.[5]

References

  1. Meyer JM, Loebel AD, Schweizer E (September 2009). “Lurasidone: a new drug in development for schizophrenia”. Expert Opinion on Investigational Drugs 18 (11): 1715–26. doi:10.1517/13543780903286388. PMID 19780705.
  2.  “FDA approves Latuda to treat schizophrenia in adults” (Press release). USFDA. 2010-10-28. Retrieved October 29, 2010.
  3. FDA Clinical Review of lurasidone for the treatment of schizophrenia Nakamura M, Ogasa M, Guarino J, et al. (June 2009).
  4. “Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial”. The Journal of Clinical Psychiatry 70 (6): 829–36. doi:10.4088/JCP.08m04905. PMID 19497249.
  5.  Ishiyama T, Tokuda K, Ishibashi T, Ito A, Toma S, Ohno Y (October 2007). “Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test”. European Journal of Pharmacology 572 (2-3): 160–70. doi:10.1016/j.ejphar.2007.06.058. PMID 17662268.
  6. Enomoto T, Ishibashi T, Tokuda K, Ishiyama T, Toma S, Ito A (January 2008). “Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats”. Behavioural Brain Research 186 (2): 197–207. doi:10.1016/j.bbr.2007.08.012. PMID 17881065.
  7. Dainippon Sumitomo Pharma (August 26, 2009). “Lurasidone Demonstrated Efficacy in Treating Patients with Schizophrenia in Pivotal Phase III Study”.
  8.  “Latuda: Prescribing Information”. Psychotherapeutic Drugs. Retrieved 2010-12-17.
  9.  “Latuda”. Drugs.com. Retrieved 2010-12-17.
  10.  “Atypical antipsychotics and risk of cerebrovascular accidents”. Retrieved 28 July 2012.

LATUDA® (lurasidone hydrochloride) Schizophrenia，Bipolar disorder

  • Developed in-house
  • LATUDA® (lurasidone hydrochloride) is an atypical antipsychotic agent which is believed to have an affinity for dopamine D2, serotonin 5-HT2A and serotonin 5-HT7 receptors where it has antagonist effects. In addition, LATUDA is a partial agonist at the serotonin 5-HT1A receptor and has no appreciable affinity for histamine or muscarinic receptors. In the clinical trials supporting the U.S. FDA approval, the efficacy of LATUDA for the treatment of schizophrenia was established in four, short-term (6-week), placebo-controlled clinical studies in adult patients who met DSM-IV criteria for schizophrenia. In these studies, LATUDA demonstrated significantly greater improvement versus placebo on the primary efficacy measures [the Positive and Negative Syndrome Scale (PANSS) total score and the Brief Psychiatric Rating Scale-derived from PANSS (BPRSd)] at study endpoint. A total of five short-term placebo controlled clinical trials contributed to the understanding of the tolerability and safety profile of LATUDA. LATUDA was approved for the treatment of schizophrenia by the U.S. Food and Drug Administration (FDA) in October 2010, and launched by Sunovion in February 2011 in the U.S. Launched in Canada for the treatment of schizophrenia in September 2012.
  • Development stage:
    Schizophrenia: Submitted MAA (Europe: Co-development with Takeda Pharmaceutical)
    Phase III in Japan
    In addition, Phase III study is ongoing in the U.S., Europe, etc. to test the hypothesis that LATUDA is effective in the long term maintenance treatment of schizophrenia.
    Bipolar I Depression: Submitted in the U.S. and Canada.
    In addition, plans to submit an MAA in Europe through Co-development with Takeda Pharmaceutical. (Phase III in Europe).
    Bipolar Maintenance: Phase III in the U.S. and Europe, etc.
    MDD with mixed features: Phase III in the U.S

MAA EU -GSK submits diabetes drug Eperzan, albiglutide in EU

March 9, 2013 3:36 am / 4 Comments on MAA EU -GSK submits diabetes drug Eperzan, albiglutide in EU


MAA EU =marketing authorisation application EU

MAR 08 2013

GSK submits diabetes drug albiglutide in EU

GlaxoSmithKline has announced the submission of a marketing authorisation application for albiglutide, which will have the brand name Eperzan, to the European Medicines Agency.

The filing of albiglutide, a once-weekly treatment for type 2 diabetes, comes almost two months after it was filed in the USA. The drug is a GLP-1 receptor agonist, the same class of injectable treatments dominated by Novo Nordisk’s once-a-day Victoza (liraglutide), twice-daily Byetta (exenatide) and an extended-release formulation of the latter, Bydureon. They were developed and sold by Amylin, which was then acquired by  Bristol-Myers Squibb and AstraZeneca.

The filing is based in part on a study which assessed albiglutide against Merck & Co’s DPP-4 inhibitor Januvia (sitagliptin) which showed that GSK’s drug showed clinically and statistically significant reductions in HbA1c from baseline and superiority versus the US firm’s diabetes blockbuster. However in data from a late-stage study released in November 2011, albiglutide failed to show non-inferiority to Victoza and a number of analysts believe GSK will have its work cut out to grab a decent share of the GLP-1 market.

Albiglutide is a glucagon-like peptide-1 agonist (GLP-1 agonist) drug under investigation by GlaxoSmithKline for treatment of type 2 diabetes. It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin.

Albiglutide has a half-life of four to seven days, which is considerably longer than the other two GLP-1 analogs approved for market use, exenatide (Byetta) and liraglutide (Victoza).[1] [2] GLP-1 drugs are currently only available for subcutaneous administration on a daily basis, so a GLP-1 drug with a longer half-life is desirable. Such a drug would only need to be injected biweekly or weekly instead of daily, reducing the discomfort and inconvenience of GLP-1 administration considerably.

It has not yet been determined whether albiglutide is as effective an antidiabetic agent as GLP-1 drugs currently on the market, and final data remain to be published regarding the incidence of adverse effects related to the drug. To evaluate the efficacy and safety of the drug, albiglutide is undergoing eight Phase III clinical trials. Four of these trials should report useful data by end 2010.[3]

Phase 2 SMP-986(afacifenacin fumarate) Overactive bladder/ Dainippon Sumitomo Pharma and Nippon Shinyaku conclude a license agreement for SMP-986, a therapeutic agent for urology

March 9, 2013 1:48 am / 3 Comments on Phase 2 SMP-986(afacifenacin fumarate) Overactive bladder/ Dainippon Sumitomo Pharma and Nippon Shinyaku conclude a license agreement for SMP-986, a therapeutic agent for urology


877606-63-8 cas no of afacifenacin

any str error, mail to amcrasto@gmail.com

SMP-986 (afacifenacin fumarate)

(4S)-4-phenyl-3-(1-{[3-(trifluoromethoxy)phenyl]methyl}piperidin- 4-yl)-3,4-dihydroquinazolin-2(1H)-one muscarinic receptor antagonist

  • Developed in-house
  • SMP-986 possesses the dual pharmacological actions of muscarinic receptor antagonism (non-selective) and inhibition of the bladder afferent pathway through Na+-channel blockade. This compound is being evaluated for its ability to ease urinary urgency and reduce the frequency of both urination and incontinence. The compound has also exhibited the potential to have lower incidence of side effects related to muscarinic receptor antagonism, such as dry mouth.
  • Development stage: Phase II in the U.S. and Europe. Phase II in Japan

7 mar 2013

Dainippon Sumitomo Pharma Co., Ltd. (DSP) and Nippon Shinyaku Co., Ltd. Announce they have concluded a license agreement for exclusive rights to develop, manufacture and commercialize SMP-986 in Japan, a new therapeutic agent for overactive bladder created by DSP.

Completing Phase 2 studies in Japan, Europe and the U.S., DSP was searching for a partner with a strong presence in urology. As a result, DSP chose Nippon Shinyaku as its best partner for the Japanese market.
Under this agreement, Nippon Shinyaku obtains exclusive rights to develop, manufacture and commercialize SMP-986 in Japan for general urological diseases. In return, Nippon Shinyaku will pay DSP an upfront fee and make development milestone payments. In addition, after launch Nippon Shinyaku will also pay DSP royalties according to sales amounts and milestone payments in accordance with sales goals.
SMP-986 possesses the dual pharmacological actions of muscarinic receptor antagonism and inhibition through Na+-channel blockade. In the future, Nippon Shinyaku plans to proceed with the development of SMP-986 to obtain approval for the indication of nocturia

DCVax®-Direct Phase I/II Trial For All Inoperable Solid Tumors Is Expected To Produce Ongoing Results In 2013

March 8, 2013 11:57 am / 1 Comment on DCVax®-Direct Phase I/II Trial For All Inoperable Solid Tumors Is Expected To Produce Ongoing Results In 2013


BETHESDA, Md., \

March 5, 2013 Northwest Biotherapeutics  (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that its Phase I/II  DCVax-Direct clinical trial for all inoperable solid tumor cancers is planned to begin within approximately the next sixty days.  As a Phase I/II trial, this trial is not blinded and the results will be seen as the trial proceeds.  With an efficacy endpoint of tumor regression (i.e., tumor shrinkage or elimination), this innovative trial is expected to yield meaningful ongoing results by the second half of 2013.

This clinical trial is approved by the FDA for all types of solid tumor cancers (i.e., cancers in any tissues of the body), and is configured to provide rapid results.  In the Phase I portion, it will test both safety and a variety of dosing regimes, and will do so in multiple different cancers – avoiding the need to conduct separate Phase I studies in each such cancer, as is usually the case.  Then, the trial will go directly into the Phase II portion, testing for efficacy, without the need for another FDA review.

DCVax®

All immune responses start in the same way that involves initially a single cell type, the dendritic cell (DC). This cell functions like the General of an army, in that it directs all ensuing activities of the immune response. The immune system is like an army with many divisions, and multiple soldiers with various types of weapons. When an invader, which could be a virus, bacteria, or a cancer cell, encounters a DC the result is that the DC consumes or eats the invader and chops it into small pieces. In the process, the DC becomes activated and starts traveling to the lymph node. In the lymph nodes the DC elicits a cascade of events eventually involving the entire army that leads to a full-blown immune response. Importantly, the nature of the invader and the nature of the DC activation dictate the type of immune response: the DC is the general of the army who directs all the soldiers to work in synchrony, and who determines which weapons to use to best defeat the enemy. We believe that preparing the DC outside the body, as done for DCVax® products, allows the greatest degree of control and begins the immune response in the natural fashion leading to the most complete attack on the foreign invader.

Different Approaches

We believe that the optimal way to arrive at the most effective immune response is through the control of the DC. Most traditional immunization approaches, including traditional virus, specific antigen or peptide vaccines as well as some that are used for immunotherapy of cancer, try to control the already existing DC in the body, or they try to modulate only one arm of the immune system. The immunogen, i.e. the virus, specific antigen, peptide or the cancer cells used to prepare the vaccine, is in those cases injected into the body in a formulation that aims at targeting and activating local DC. Examples are viral, specific antigen or peptide vaccines formulated with adjuvant, or killed tumor cells alone or modified to produce the DC mobilizing protein GM-CSF. In these instances, it is left to chance as to whether the immunogen arrives at the DC, whether the DC are properly activated, and effectively migrate to lymph nodes to produce an effective immune response. We believe that the failure of several recent clinical trials may be the result of the inability of these other approaches to effectively mount a natural and robust immune response.

Treatments that use only a single division of the immune system may employ only large amounts of T cells, or a single (monoclonal) antibody. DCVax® products are being developed to activate all aspects of the immune response, both cellular and antibody, thus potentially providing a broader and longer lasting immune and clinical response. Northwest Biotherapeutics’ products are deigned as pure, activated DC loaded with the immunogen as would naturally occur, and that are capable of migrating to lymph nodes. The intended result is a very robust, and full immune response consisting of both a specific cellular T cell response and a specific antibody response against the cancer associated antigen. Data obtained in our Phase I and Phase II clinical trials suggest that such response may occur and may translate into a clinical benefit.

Cancer and the Immune System

Cancer cells produce many substances that shut down the immune response, as well as substances that paralyze the DC that are resident in the body. We believe therefore that the optimal time for controlling cancer growth by activating the immune system is at the time when tumor burden is low. Northwest Biotherapeutics targets patients with brain cancer following surgery, radiation and chemotherapy, and hormone independent prostate cancer patients with no detectable tumor growth. This approach aims at inducing powerful immune responses to control progression of the disease.

Manufacturing

Northwest Biotherapeutics has focused on solving many of the challenges that are typically associated with producing personalized products that consist of living cells. The Company’s new automated cell processing system allows high-throughput production of products for a fraction of the historical cost.

  • DCVax® products contain pure DC
  • The DC in DCVax® are prepared outside the body, which eliminates many uncontrollable variables, and are subjected to a potency test designed to ensure that the DC administered to the patient are capable of eliciting an immune response
  • DCVax® is used in patients with low tumor burden
  • DCVax® products can be manufactured in a cost-efficient manner

ViiV Healthcare presents phase III SAILING study data of dolutegravir vs raltegravir in treatment-experienced adults with HIV-1

March 8, 2013 11:45 am / 2 Comments on ViiV Healthcare presents phase III SAILING study data of dolutegravir vs raltegravir in treatment-experienced adults with HIV-1


Dolutegravir

Identifiers
CAS number 1051375-16-6 

8 TH MATCH 2013

ViiV Healthcare, a global specialist HIV company established in November 2009 by GSK and Pfizer dedicated to delivering advances in treatment and care for people living with HIV, has announced 24-week data from the phase III SAILING (ING111762) study evaluating the investigational integrase inhibitor dolutegravir in patients with HIV-1 who are failing on current therapy, but had not been treated with an integrase inhibitor.

At 24 weeks, 79% of study participants receiving the once-daily dolutegravir regimen were virologically suppressed (HIV-1 RNA <50 c/mL) vs. 70% of participants on the twice-daily raltegravir regimen. This difference in response was statistically significant with a 95% confidence interval for the difference of 3.4% to 15.9% (p=0.003).

The SAILING study was designed to demonstrate non-inferiority of a regimen containing dolutegravir versus raltegravir (both with up to two background agents) and the analysis met this criterion; statistical superiority was concluded as part of a pre-specified testing procedure. These data were presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia.

Differences in treatment outcome in favour of the dolutegravir arm were driven by greater virologic response: at Week 24, 15% of patients receiving the dolutegravir regimen had virologic non-response vs. 24% of patients receiving the raltegravir regimen.  In addition, fewer subjects failed therapy with integrase inhibitor resistance on dolutegravir (n=2) than on raltegravir (n=10, p=0.016).

Overall, the tolerability of dolutegravir (DTG) was similar to that of raltegravir (RAL). At 24 weeks, 2% of subjects on the dolutegravir regimen discontinued due to adverse events (AEs) vs. 4% of subjects on the raltegravir regimen. The rate of drug-related AEs was similar for both arms (DTG 20%, RAL 23%) and commonly reported AEs (defined as events that occurred in more than 10% of subjects) were similar on both arms, namely diarrhoea (20% DTG, 17% RAL) and upper respiratory tract infection (11% DTG, 8% RAL).

“People living with HIV who have developed resistance to more than one antiretroviral drug class face increasingly narrow treatment options and clinical decisions become increasingly complex. We welcome these initial results supporting the efficacy and tolerability of dolutegravir as a potentially useful addition in the management of HIV in treatment-experienced patients.” said John Pottage, chief scientific and medical officer, ViiV Healthcare.  “These encouraging data were included as part of the comprehensive clinical data package supporting recent regulatory submissions for dolutegravir and we look forward to receiving the primary analysis at 48 weeks in due course.”

The primary objective of the ongoing double-blind, double-dummy phase III SAILING study is to demonstrate the antiviral activity of once-daily dolutegravir 50mg compared to twice-daily raltegravir 400mg over 48 weeks in HIV-1 infected, antiretroviral-experienced, integrase inhibitor-naïve adults. At baseline, 715 study participants were randomised 1:1 to receive either dolutegravir or raltegravir plus investigator-selected background regimen of no more than 2 agents, one of which was fully active. All subjects had documented genotypic or phenotypic resistance to agents from at least two antiretroviral therapy drug classes, and ongoing virologic replication.  Median baseline HIV-1 RNA levels were 4.18 log10 c/mL and median baseline CD4+ cell counts were 200 cells/mm3. The study population included 32% women, 42% were of African American/African heritage, and 46% of study participants were classified as CDC Class C (patients who have one or more AIDS-defining illness). The 48-week primary analysis of this study will be presented at a future scientific meeting.

S/GSK1349572 (dolutegravir, DTG) is an investigational integrase inhibitor currently in development for the treatment of HIV; it does not require an additional pharmacokinetic boosting drug to be added to the regimen. Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.

SAILING is the fourth phase III dolutegravir study reporting in 2012 and 2013. Data from the two studies in treatment-naïve populations, SPRING-2 (ING113086) and SINGLE (ING114467), were announced in April and July of 2012 respectively. Data from VIKING-3 (ING112574) in integrase inhibitor-resistant patients were announced in November 2012. Dolutegravir is not yet approved as a treatment for HIV or any other indication anywhere in the world.

Dolutegravir[1] is an experimental new drug under investigation for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Also known as S/GSK1349572 or just “572”, the drug is under development by GlaxoSmithKline (GSK). Studies have shown dolutegravir to be effective in patients with resistance to the integrase inhibitor, raltegravir.[2] Clinical trials are underway to support dolutegravir in combination with abacavir and lamivudine, in a new new fixed dose combination called 572-Trii.[3] In February, 2013 the Food and Drug Administration announced that it would fast track dolutegravir’s approval process.[4]

Results from the 96-week comparison with efavirenz, SPRING-1, showed dolutegravir 50mg orally to be effective at reducing HIV viral load and raising CD4 counts in integrase-naive patients. [5]

References

  1. [1] American Medical Association (AMA), STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL (Dolutegravir) Accessed 3 December 2011.
  2.  Dolutegravir (“572”) Holds Up in Heavily Raltegravir-Resistant Patients, Phase 2B Study Finds Nelson Vergel. The Body PRO. Accessed 23 April 2011.
  3.  Shionogi-ViiV Healthcare Starts Phase 3 Trial for “572-Trii” Test positive airwave. The Body PRO. Accessed 23 April 2011.
  4.  “GSK wins priority status for new HIV drug in U.S”. Reuters. 16 February 2013. Retrieved 18 February 2013.
  5. Horn, Tim. ViiV’s Dolutegravir Continues to Show Well After 96 Weeks, Versus Sustiva, for First-Time Treatment. AIDSmeds.com 7 Mar 2012. Accessed 14 Mar 2012.

NDA FDA-Nuvo reports FDA response to PENNSAID 2% , diclofenac sodium topical solution, 2% w/w

March 8, 2013 3:30 am / 1 Comment on NDA FDA-Nuvo reports FDA response to PENNSAID 2% , diclofenac sodium topical solution, 2% w/w


DICLOFENAC

 

 

PENNSAID 2%

7 MAR 2013

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Nuvo Research’s US licensing partner, Mallinckrodt, following the review of Mallinckrodt’s New Drug Application (NDA) for diclofenac sodium topical solution, 2% w/w (PENNSAID 2%).

FDA in the letter mentioned that it requires Mallinckrodt’s complete pharmacokinetic study comparing PENNSAID 2% to original PENNSAID 1.5%.

FDA denied to review the similar pharmacokinetic studies submitted by Mallinckrodt with the NDA, as the reserve samples were not retained at the clinical site.

Pharmacokinetic studies are standard studies conducted during a drug development program to identify the total exposure or the amount of drug that reaches the blood stream after a patient receives both single and multiple doses of the product.

Mallinckrodt has suggested Nuvo that it expects to complete the study and submit the results to the FDA in the third quarter of 2013, and that it anticipates the FDA will provide a formal response to the filing within 6 months thereafter.

Nuvo’s Pain Group president Dr. Bradley Galer said with the new FDA’s letter the firm was disappointed that PENNSAID 2% will not be approved in this review cycle.

“We are pleased that the FDA has outlined a clear pathway to approval that we believe can be completed in a relatively short time frame,” Galer added.

“Upon approval, PENNSAID 2% will be the first and only topical NSAID in the U.S. featuring twice per day dosing and a metered dose pump bottle.”

Phase 3-Trius Therapeutics will soon be reporting data from its second phase III trial of Tedizolid

March 7, 2013 1:08 pm / 2 Comments on Phase 3-Trius Therapeutics will soon be reporting data from its second phase III trial of Tedizolid


ChemSpider 2D Image | Torezolid | C17H15FN6O3

Tedizolid

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

  • Molecular Formula: C17H15FN6O3
  • Average mass: 370.337799

856866-72-3  cas no

Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701”, while the active ingredient is called “TR-700”.[4][5]

March 5 2013

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

 

  1. “Trius grows as lead antibiotic moves forward”. 31 Oct 2011.
  2. “Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.
  3. http://clinicaltrials.gov/ct2/results?flds=Xf&flds=a&flds=b&term=tedizolid&phase=2&fund=2&show_flds=Y
  4. PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
  5. PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

Phase 1-Sangamo Presents New Clinical Data at CROI 2013 Demonstrating Persistent Immune System Improvements After Treatment With ZFN Therapeutic(R) SB-728-T

March 7, 2013 1:03 pm / 2 Comments on Phase 1-Sangamo Presents New Clinical Data at CROI 2013 Demonstrating Persistent Immune System Improvements After Treatment With ZFN Therapeutic(R) SB-728-T


 

The gene therapy diminished the levels of virus and eradicated in patients having naturally occurring mutation of gene, found a preliminary trail of HIV treatment. The first phase of very small trail tested the SB-728-T gene treatment that is intended to interrupt theCCR5 gene used by HIV to contaminate immune system cells.

The first clinical trial using zinc-finger nucleases to provide long-term resistance to HIV-1 infection has been given the go-ahead by the US Food and Drug Administration. Sangamo BioSciences of Richmond, California, and its clinical partner, the University of Pennsylvania, have begun enrolling the first 12 people in a phase 1 clinical trial to evaluate SB-728-T, a novel zinc-finger DNA-binding nuclease that permanently disrupts the CCR5 gene on CD4+ T cells (Nat. Biotechnol. 26, 808–816, 2008

Data Demonstrate that SB-728-T Possesses Necessary Immunologic Properties to Support a ‘Functional Cure’ for HIV/AIDS

RICHMOND, Calif., March 6, 2013

Sangamo BioSciences, Inc. announced new data from its program to develop a ‘functional cure’ for  HIV/AIDS  in two presentations at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), held in Atlanta from March 3 to 6, 2013.

The first presentation described data from the SB-728-T Phase 1 study (SB-728-902, Cohorts 1-3) demonstrating that SB-728-T treatment of HIV-infected subjects leads to durable reconstitution of the immune system driven by increases in total CD4+ central memory T-cells (TCM) and CCR5-protected TCM. TCM are long-lived, self-renewing cells that have the ability to remember and react against foreign antigens including HIV.  The data also showed that certain cell surface marker and gene expression profiles may predict which patients will likely respond best to SB-728-T treatment.

About Sangamo


Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. Sangamo’s other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington’s disease and  hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs).  Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington’s disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company’s website atwww.sangamo.com.

Phase III Study of Oral Laquinimod for Relapsing-Remitting Multiple Sclerosis

March 7, 2013 1:00 pm / 2 Comments on Phase III Study of Oral Laquinimod for Relapsing-Remitting Multiple Sclerosis


Laquinimod

5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-
N-phenyl-1,2-dihydroquinoline-3-carboxamide

Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is currently being investigated as an oral treatment for multiple sclerosis (MS).

Laquinimod is the successor of Active Biotech’s failed experimental immunomodulator linomide.[1]

The compound has been investigated in two Phase II trials using successive magnetic resonance scans (MRI). Laquinimod seems to be able to reduce the MS disease activity on MRI.[2][3] However, the response to a given dose was discrepant between both studies.[4]

Phase III studies for MS started in December 2007.[5] In 2011, Teva announced its clinical trials involving laquinimod had failed, being unable to significantly reduce relapses into MS among patients beyond a placebo.[6] However, the final results of above mentioned phase III trial proved oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis [7]

Mar 6, 2013 –

CONCERTO Study Enrolling Patients Globally to Evaluate Impact of Laquinimod on Disability Progression

Teva Pharmaceutical Industries Ltd.  and Active Biotech  announced today enrollment of the first patient in the CONCERTO study – the third Phase III placebo-controlled study designed to evaluate the efficacy, safety and tolerability of once-daily oral laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS). The primary outcome measure of CONCERTO will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS).

“Previous Phase III studies in more than 2,400 people with RRMS suggest a unique profile of laquinimod, directly affecting the neurodegenerative processes that lead to disability progression, the main concern in the treatment of RRMS,” said CONCERTO principal investigator, Dr. Timothy Vollmer, Professor of Neurology, University of Colorado Denver, Medical Director of the Rocky Mountain Multiple Sclerosis Center, and Co-Director of the RMMSC at Anschutz. “We are currently enrolling patients in this third pivotal study to further examine the clinical benefits of laquinimod on disability progression, the primary endpoint of the CONCERTO trial, and brain atrophy, at both the previously studied 0.6 mg dose, and now a higher 1.2 mg dose.”

The multinational, randomized, double blind placebo-controlled study will aim to enroll approximately 1,800 patients at more than 300 sites globally (http://clinicaltrials.gov/show/NCT01707992). Along with the primary endpoint of time to confirmed disability progression, the study will also examine the impact of laquinimod on endpoints such as percent change in brain volume and other clinical and MRI markers of disease activity.

“For nearly 30 years, Teva has been focused on improving the lives of people with multiple sclerosis by delivering innovative treatment options that address this complex disease,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The CONCERTO study demonstrates our commitment to collaborating with MS communities worldwide to further develop laquinimod and address unmet patient needs.”

ABOUT LAQUINIMOD

Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.

In addition to the MS clinical studies, laquinimod is currently in clinical development for Crohn’s disease and Lupus.

ABOUT CONCERTO

CONCERTO is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by an active treatment phase, to evaluate the efficacy, safety and tolerability of two doses of oral administration of laquinimod 0.6 mg/day or 1.2 mg/day in subjects with RRMS. This third Phase III laquinimod study will evaluate laquinimod in approximately 1,800 patients for up to 24 months, after which patients will continue to an active treatment period with laquinimod for an additional 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity.

ABOUT MULTIPLE SCLEROSIS

MS is the leading cause of neurological disability in young adults. It is estimated that more than 400,000 people in the United States are affected by the disease and that two million people may be affected worldwide. Multiple sclerosis is a degenerative disease of the central nervous system in which inflammation and axonal damage and loss result in the development of progressive disability.

ABOUT TEVA

Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) is a leading global pharmaceutical company, committed to increasing access to high-quality healthcare by developing, producing and marketing affordable generic drugs as well as innovative and specialty pharmaceuticals and active pharmaceutical ingredients. Headquartered in Israel, Teva is the world’s leading generic drug maker, with a global product portfolio of more than 1,000 molecules and a direct presence in about 60 countries. Teva’s branded businesses focus on CNS, oncology, pain, respiratory and women’s health therapeutic areas as well as biologics. Teva currently employs approximately 46,000 people around the world and reached $20.3 billion in net revenues in 2012.

ABOUT ACTIVE BIOTECH

Active Biotech AB is a biotechnology company with focus on autoimmune/inflammatory diseases and cancer. Projects in or entering pivotal phase are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, TASQ for prostate cancer as well as ANYARA for use in cancer targeted therapy, primarily of renal cell cancer. In addition, laquinimod is in Phase II development for Crohn’s and Lupus. Further projects in clinical development comprise the two orally administered compounds, 57-57 for SLE & Systemic Sclerosis and RhuDex(TM) for RA. Please visit http://www.activebiotech.com for more information.

  1.  Tan IL, Lycklama à Nijeholt GJ, Polman CH et al. (April 2000). “Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials”. Mult Scler 6 (2): 99–104. PMID 10773855.
  2. Comi G, Pulizzi A, Rovaris M et al. (June 2008). “Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study”. Lancet 371 (9630): 2085–2092. doi:10.1016/S0140-6736(08)60918-6. PMID 18572078.
  3.  Polman C, Barkhof F, Sandberg-Wollheim M et al. (March 2005). “Treatment with laquinimod reduces development of active MRI lesions in relapsing MS”. Neurology 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69. PMID 15781813.
  4. Keegan BM, Weinshenker BG (June 2008). “Laquinimod, a new oral drug for multiple sclerosis”. Lancet 371 (9630): 2059–2060. doi:10.1016/S0140-6736(08)60894-6. PMID 18572062.
  5. ClinicalTrials.gov NCT00509145 Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (ALLEGRO)
  6. Kresege, Naomi (1 August 2011). “Teva’s Copaxone Successor Fails in Latest Clinical Trial”. Bloomberg. http://www.bloomberg.com/news/2011-08-01/teva-s-oral-multiple-sclerosis-drug-fails-to-meet-goal-of-clinical-trial.html. Retrieved 2 August 2011. “Teva Pharmaceutical Industries Ltd. (TEVA)’s experimental multiple sclerosis pill failed to reduce relapses more than placebo in a clinical trial, dealing a blow to the company’s effort to find a successor to an older drug.”
  7. (Comi et al. N Engl J Med 2012;366:1000).

EP 1073639; JP 2002513006; US 6077851; WO 9955678

5-Chloroisatoic anhydride (I) is alkylated with iodomethane and NaH to afford (II). Subsequent condensation of anhydride (II) with the malonic monoamide (III) in the presence of NaH in hot DMA furnishes the target quinoline carboxamide.

…

Reaction of 2-amino-6-chlorobenzoic acid (I) with phosgene and NaHCO3 in dioxane gives 5-chloroisatoic anhydride (II), which is methylated by means of iodomethane and NaH in DMF to yield 5-chloro-1-methylisatoic anhydride (III). Finally, anhydride (III) is condensed with the malonic monoamide (IV) by means of NaH in hot dimethylacetamide. Alternatively, condensation of anhydride (III) with ethoxy malonyl chloride (V) by means of NaOMe and triethylamine in dichloromethane affords 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3- carboxylic acid ethyl ester (VI), which is finally condensed with N-ethylaniline (VII) in refluxing toluene. Alternatively, ester (VI) is hydrolyzed by means of concentrated HCl in hot Ac2O to give the carboxylic acid (VIII), which is finally condensed with N-ethylaniline (VII) by means of SOCl2 and TEA in dichloromethane

Post navigation

← Older posts Newer posts →