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ROLAPITANT, ロラピタント

December 3, 2018 9:31 am / 1 Comment on ROLAPITANT, ロラピタント

ROLAPITANT HYDROCHLORIDE

Rolapitant HCl
Rolapitant hydrochloride
Sch 619734
SCH619734
UNII-57O5S1QSAQ

(5S ,8S)-8-[[(1R)-1-[3 ,5-
Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7-
diazaspiro[4.5]decan-2-one hydrochloride monohydrate.

CAS 914462-92-3

Empirical Formula: C25H26F6N2O2 · HCl · H2O, Molecular Weight: 555

USAN Name: Rolapitant hydrochloride, INN Name: rolapitantum or rolapitant

CAS Number: 552292-08-7 (rolapitant free base); 914462-92-3 (rolapitant HCl monohydrdate).

ChemSpider 2D Image | rolapitant | C25H26F6N2O2

Rolapitant

Molecular FormulaC₂₅H₂₆F₆N₂O₂
Average mass500.477 Da

(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluorométhyl)phényl]éthoxy}méthyl)-8-phényl-1,7-diazaspiro[4.5]décan-2-one

1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, (5S,8S)-

552292-08-7 [RN]

8882

NLE429IZUC

SCH 619734

SCH-619734

Varubi®

UNII-NLE429IZUC

(5S,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one

Rolapitant Hydrochloride Hydrate was approved by the U.S. Food and Drug Administration (FDA) on Sep 1, 2015. It was developed by Tesaro, then marketed as Varubi^® by Tesaro in US.

Rolapitant Hydrochloride Hydrate is a selective and competitive antagonist of human substance P/NK1 receptors used to treat chemotherapy-induced nausea and vomiting.
Varubi^® is available as tablet for oral use, containing 90 mg of free Rolapitant. The recommended dose is 180 mg approximately 1 to 2 hours prior to the start of chemotherapy.

In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy, rolapitant shows no inhibition of CYP3A4, eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h), providing potential opportunities for single- and prechemotherapy-based treatments.

In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.

It is in late-stage trials of its drug rolapitant, which showed promising mid-stage results in reducing nausea and vomiting in patients undergoing chemotherapy

Rolapitant hydrochloride is a tachykinin neurokinin 1 (NK1) antagonist in phase III clinical trials at Tesaro for the prevention of chemotherapy-induced nausea and vomiting (CINV). Phase II clinical trials are also under way at OPKO for this indication. At Merck & Co., phase II clinical studies were also under way for the treatment of chronic idiopathic cough and for the prevention of chemotherapy-induced nausea; however, no recent developments have been reported for these indications.

NK1 is a G-protein coupled receptor found in the central and peripheral nervous systems. Substance P is the endogenous ligand for this receptor, whose activation leads to the production of inositol triphosphate. NK1 is believed to be involved in the emetic response.

The drug candidate was originally developed by Schering-Plough (now Merck & Co.), and in 2009 it was licensed to OPKO for the prevention of nausea and vomiting related to cancer chemotherapy and surgery. In 2010, rolapitant was licensed by OPKO to Tesaro on a worldwide basis for the prevention of chemotherapy-induced nausea and vomiting.

Rolapitant is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. (source: Pharmacol Biochem Behav.2012 Mar 31.

Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions. A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation.RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ≤ 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.

Rolapitant (INN,^[2] trade name Varubi /vəˈruːbi/ və-ROO-bee in the US and Varuby in Europe) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK₁ receptor antagonist (antagonist for the NK₁ receptor).^[3] It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.^[4]^[5]^[6]^[7

Medical uses

Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.^[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT₃ antagonist.^[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.^[9] Under the European approval, it is contraindicated in combination with St. John’s Wort, which is expected to accelerate inactivation of rolapitant.^[8]

Side effects

In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT₃ antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT₃ antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).^[9]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.^[8]

Interactions

Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphanhave increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.^[8]

Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.^[8]

Pharmacology

Pharmacodynamics

Both rolapitant and its active metabolite M19 block the NK₁ receptor with high affinity and selectivity: to block the closely related receptor NK₂ or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.^[10]

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).^[8] The stereochemistry of the hydroxyl group is unknown.

Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.^[8]

It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.^[8]

Chemistry

The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.^[10]

Patents

WO 2003051840

PATENT

WO 2008118328

The preparation of diazaspirodecan-2-ones for example, 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) has been described in U.S. Pat. No. 7,049,320 (the ‘320 patent), issued May 23, 2006, the disclosure of which is incorporated herein in its entirety by reference.

The compounds described in the ‘320 patent are classified as tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (herein, “NK-1” receptor antagonists). Other NK₁receptor antagonists and their synthesis have been described, for example, those described in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001) and in published international application no. WO05/100358, each of which are incorporated herein in their entirety by reference.

“NK-1” receptor antagonists have been shown to be useful therapeutic agents, for example, in the treatment of pain, inflammation, migraine, emesis (vomiting), and nociception. Among many compounds disclosed in the above-mentioned ‘320 patent are several novel diazaspirodecan-2-ones, including the compound of Formula I, which are useful in the treatment of nausea and emesis associated with chemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I described in the ‘320 patent generally follows Scheme I in the provision of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxyl}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.

The process for the preparation of the compound of Formula I described in the ‘320 patent is carried out in 18 individual steps from commercially available starting materials (see the ‘320 patent at col. 43, line 55 to col. 45, line 20; col. 75. line 55 to col. 80, line 21; col. 90 lines 35 to 63; and col. 98, line 1 to col. 99. line 24). In many steps of the process described in the ‘320 patent, intermediate compounds must be isolated or isolated and purified before use in a subsequent step, often utilizing column chromatography for this purpose.

PATENT

US7049320

Examples 72a and 72b

Step 1:

To a solution of crude Compound 53 (19 g) in CH₂Cl₂(300 ml) at RT, DIEA (15 ml, 0.087 mol) was added, followed by triphosgene (4.34 g, 0.015 mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2:

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH₄(1.26 g, 0.058 mol) was added in small portions. The mixture was stirred at RT for 18 h before quenching with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61 (12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8 m[, 0.096) in CH₂Cl₂(300 ml) at −78° C. under N₂. The mixture was stirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g, 0.012 mol) in CH₂Cl₂(100 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et₃N (23.5 ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃solution. Layers were separated and the aqueous was extracted with CH₂Cl₂(150 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C., methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. The mixture was stirred at 0° C. for 15 min and a solution of aldehyde in THF (100 ml) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester was dissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g, 10% on carbon) was added. The mixture was shaken under H₂(50 psi) for 2 days. Catalytic amount of Pd(OH)₂(20% on carbon) was then added to the mixture and the mixture was again shaken under H₂(50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH₂Cl₂(200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0° C. before it was neutralized with saturated NaHCO₃solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH₃OH (50 ml) and a catalytic amount of K₂CO₃(166 mg, 0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1]⁺=501.1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1]⁺=501.1.

PATENT

US8552191

Figure US08552191-20131008-C00028

Figure US08552191-20131008-C00029

Figure US08552191-20131008-C00030

Figure US08552191-20131008-C00031

Figure US08552191-20131008-C00032

Example 6 Preparation of Formula I Compound Salt: (5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride monohydrate

…………………

Figure US08552191-20131008-C00016

Figure US08552191-20131008-C00017

https://www.google.it/patents/US8552191?hl=it&dq=WO+2008118328&ei=alDCUs-_KYiIrQeg3oCwDw&cl=en

……………

update added

By RTT News, May 12, 2014,

(RTTNews.com) – TESARO Inc. ( TSRO ) announced positive top-line results from the third and final Phase 3 trial of rolapitant, an investigational neurokinin-1 or NK-1 receptor antagonist in development for the prevention of chemotherapy-induced nausea and vomiting (CINV).

The rolapitant arm in this trial, which enrolled patients receiving cisplatin-based, highly emetogenic chemotherapy or HEC, successfully achieved statistical significance over the standard therapy arm for the primary and all secondary endpoints. The adverse event profile for rolapitant remains consistent with that seen in previous clinical studies.

The third Phase 3 study of rolapitant was an international, multicenter, randomized, double-blind, active-controlled study that enrolled 532 cancer patients receiving cisplatin-based chemotherapy regimens at a dose equal to or greater than 60 mg/m2. Patients were randomized to receive either control, which consisted of a 5-HT3 receptor antagonist plus dexamethasone, or 200 milligrams of oral rolapitant plus control. The rolapitant arm in this study successfully achieved statistical significance over the control arm for the primary endpoint of complete response (CR) in the delayed phase of CINV.

In addition, the rolapitant arm also successfully achieved statistical significance over the control arm for the key secondary endpoints of CR in the acute (0 to 24 hour) and overall (0 to 120 hour) phases of CINV, for the secondary endpoint of no significant nausea, and for all other secondary endpoints.

Safety and tolerability data for patients who received rolapitant were similar to the results for those who received control, and were consistent with earlier clinical studies. The most frequently observed adverse events were balanced across treatment arms and included fatigue, constipation and loss of appetite.

The company noted that preparations continue in support of a submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in mid-2014.

The oral rolapitant NDA will include data from one Phase 3 study in patients receiving moderately emetogenic chemotherapy (MEC), in addition to one Phase 2 and two Phase 3 trials in patients receiving cisplatin-based, highly emetogenic chemotherapy (HEC), including the trial announced today.

The top-line results of the Phase 3 trial in MEC and the prior Phase 3 trial in HEC were previously announced by TESARO in December 2013.

Rolapitant is an investigational agent and, as such, has not been approved by the U.S. FDA or any regulatory agencies.

CLIP

Rolapitant Hydrochloride Hydrate (Varubi)

Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents.(67) Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.(68) In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy,(69) rolapitant shows no inhibition of CYP3A4,(68)eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h),(68, 70) providing potential opportunities for single- and prechemotherapy-based treatments.(71)

Rolapitant features a fascinating molecular architecture consisting of two tetrasubstituted stereogenic carbon centers situated at the 2- and 5-carbons within a central piperidine ring and a spirocyclic array residing at the 5-position and a phenyl ring and ethereal linkage branching from the 2-position (Scheme 17). The overall synthetic strategy to secure rolapitant hydrochloride hydrate relies upon the union of two advanced chiral building blocks that contain functional groups capable of securing the central piperidine ring. These two key intermediates, pyroglutamate derivative 93 and allylic amine 94, each bear one of the essential stereocenters embedded within the structure of the active pharmaceutical ingredient.(73) The first of these advanced intermediates, amidoaldehyde 93, is generated directly by base-mediated decomposition of pyroglutamic aminal 92, which was prepared according to the route shown in Scheme 18. Subjection of 92 to triethylamine in EtOH/H₂O at ambient temperatures led to generation of chiral allyl aldehyde 93, which was not isolated but condensed immediately with amine 94 (Scheme 19) in the presence of refluxing toluene to provide divinyl imine 95, which underwent immediate reduction using NaBH(OAc)₃ in AcOH/toluene to furnish the free amine.

The free amine was converted to the corresponding tosylate monohydrate salt and triturated, providing 96 as a white crystalline powder after subjection to TsOH·H₂O in i-PrOH/H₂O. Divinyl amine 96 could then be reacted with a solution of TsOH in toluene, distilled, and directly combined with a toluene solution of Hoveyda–Grubbs second-generation catalyst (HG-II) under heating conditions, leading to the desired ring-closing metathesis product 97 as the HCl salt (85% yield over two steps) after filtration, distillation, and workup with 12N HCl. Washing of a toluene solution of 97 with aqueous NaOH and subsequent treatment of the resulting organic solution with H₂, wet Pd/C, and additional granular activated carbon (Nuchar Aquaguard) led to the fully reduced piperidine product in high yield (95%). Rolapitant hydrochloride hydrate XIII was accessed thereafter by precipitation from a solution of EtOH/i-PrOH/H₂O/HCl, providing the product as a white solid (91% yield).(73)

Scheme 17. Synthesis of Rolapitant Hydrochloride Hydrate (XIII)

Scheme 18. Synthesis of Fragment 92 of Rolapitant Hydrochloride Hydrate (XIII)

Scheme 19. Synthesis of Fragment 94 of Rolapitant Hydrochloride Hydrate (XIII)

Aldehyde precursor 92 was accessed in a four-step sequence starting from commercially available l-pyroglutamic acid 98 (Scheme 18).(73, 74) Condensation of 98 with trimethylacetaldehyde at elevated temperatures in the presence of methanesulfonic acid and NMP prior to careful addition of TFAA led to formation of pyrrolo-oxazolidone 99 in 72% yield. Deprotonation (LHMDS) and stereoselective alkylation of 99 with methyl formate, assisted by addition of copper chloride as a Lewis acid, provided access to carbaldehyde 100 in moderate yield (61%) as a single diastereomer(74) after aqueous workup and crystallization from MTBE.

Wittig olefination of aldehyde 100 (Ph₃PCH₃Br/LHMDS) followed by aqueous workup and precipitation of triphenylphosphine oxide via addition of MgCl₂ constructed an allyl lactone intermediate in 63% yield as an off-white solid, which then immediately underwent partial reduction with LiAlH(Ot-Bu)₃to smoothly deliver the key aldehyde precursor 92 in 83% yield as an inconsequential mixture of diastereomers (the stereocenter of consequence arose from the naturally occurring l-pyroglutamic acid 98), which could be employed directly in Scheme 17.(73)

Generation of 94 began with commercially available N-Cbz-(S)-phenylglycine 101 based on reports by O’Donnell and co-workers (Scheme 19).(75) Reaction of 101 with benzaldehyde dimethylacetal under Lewis acid conditions (BF₃·Et₂O) in diethyl ether led to high yield, diastereoselectivity, and enantioselectivity of trans-disubstituted oxazolidinone 102. In this case, selection of diethyl ether as a solvent was essential, as the use of DCM under similar reaction conditions favored formation of the undesired cis-product. Removal of the most acidic proton within 102 by means of KHMDS in toluene/THF, followed by alkylation with commercially available bromomethyl ether (103) in THF, led to 68% yield of 104 as a single diastereomer.(73, 76)

Reduction of 104 to the corresponding lactol (LiAlH₄/Et₂O) and subsequent ring opening with KHCO₃/H₂O in NMP yielded the intermediate aldehyde, which was readily converted to 105 via addition of the crude aldehyde solution to a mixture of Ph₃PCH₃Br and NaHMDS in toluene.

As described in Scheme 15, triphenylphosphine oxide scavenge by way of MgCl₂ enabled generation of crude product in good purity after a simple filtration. TMSI-mediated Cbz removal converted 105to the resulting free amine. Formation of the maleic acid salt enabled the product to be isolated as a crystalline solid in high purity without chromatography. Treatment of the maleate salt with NaOH in toluene provided the free base 94, which was incorporated as previously described in Scheme 17 without the need for additional purification.(73)

67 . Syed, Y. Y. Rolapitant: First Global Approval Drugs 2015, 75, 1941– 1945 DOI: 10.1007/s40265-015-0485-8
68.Duffy, R. A.; Morgan, C.; Naylor, R.; Higgins, G. A.; Varty, G. B.; Lachowicz, J. E.; Parker, E. M. Rolapitant (SCH 619734): A Potent, Selective and Orally Active Neurokinin NK1 Receptor Antagonist with Centrally-mediated Antiemetic Effects in Ferrets Pharmacol., Biochem. Behav. 2012, 102, 95– 100 DOI: 10.1016/j.pbb.2012.03.021
69.Janelsins, M. C.; Tejani, M. A.; Kamen, C.; Peoples, A. R.; Mustian, K. M.; Morrow, G. R. Current Pharmacotherapy for Chemotherapy-induced Nausea and Vomiting in Cancer Patients Expert Opin. Pharmacother. 2013, 14, 757– 766 DOI: 10.1517/14656566.2013.776541
70.Navari, R. M. Rolapitant for the Treatment of Chemotherapy-induced Nausea and Vomiting Expert Rev. Anticancer Ther. 2015, 15, 1127– 1133 DOI: 10.1586/14737140.2015.1088787
71.Romero, D. Chemotherapy Rolapitant – a New and Safer Antiemetic Agent Nat. Rev. Clin. Oncol. 2015, 12,562 DOI: 10.1038/nrclinonc.2015.144
72.(a) Schwartzberg, L. S.; Modiano, M. R.; Rapoport, B. L.; Chasen, M. R.; Gridelli, C.; Urban, L.; Poma, A.;Arora, S.; Navari, R. M.; Schnadig, I. D. Safety and Efficacy of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting after Administration of Moderately Emetogenic Chemotherapy or Anthracycline and Cyclophosphamide Regimens in Patients with Cancer: a Randomised, Active-controlled, Double-blind, Phase 3 Trial Lancet Oncol. 2015, 16, 1071– 1078 DOI: 10.1016/S1470-2045(15)00034-0

(b) Rapoport, B.; Schwartzberg, L.; Chasen, M.; Powers, D.; Arora, S.;Navari, R.; Schnadig, I. Efficacy and Safety of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting Over Multiple Cycles of Moderately or Highly Emetogenic Chemotherapy Eur. J. Cancer 2016,57, 23– 30 DOI: 10.1016/j.ejca.2015.12.023
73.Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J.; Sprague, V. M.; Zhang, F.; Xie, J.; Zeng, L.;Castellanos, L. P.; Chen, Y.; Poirier, M.; Mergelsberg, I. Process and Intermediates for the Synthesis of 8-[[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one Compounds. WO 2010028232A1, 2010.
74.Dikshit, D. K.; Maheshwari, A.; Panday, S. K. Self Reproduction of Chirality in Pyroglutamates: Reactions at α-Position with Electrophiles Tetrahedron Lett. 1995, 36, 6131– 6134 DOI: 10.1016/0040-4039(95)01160-J
75.O’Donnell, M. J.; Fang, Z.; Ma, X.; Huffman, J. C. New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the ″Self-regeneration of Stereocenters″ Method: α-Ethyl-α-phenylglycine Heterocycles 1997,46, 617– 630 DOI: 10.3987/COM-97-S83
76.Paliwal, S.; Reichard, G. A.; Wang, C.; Xiao, D.; Tsui, H.-C.; Shih, N.-Y.; Arredondo, J. D.; Wrobleski, M. L.;Palani, A. Preparation of Pyrrolidine and Piperidine Derivatives for Therapeutic Use as Neurokinin 1 (NK1) Receptor Antagonists. WO 2003051840A1, 2003.

REF

HETEROCYCLES 1997 46 PG 617 630

Paper | Special issue | Vol 46, No. 1, 1997, pp.617-630
Published online, 1st January, 1970

DOI: 10.3987/COM-97-S83

■ New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the “Self-Regeneration of Stereocenters” Method: α-Ethyl-α-phenylglycine

Martin J. O’Donnell,* Zhiqiang Fang, Xiaojun Ma, and John C. Huffman

*Department of Chemistry, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, U.S.A.

Abstract

The stereoselective room temperature ethylations of protected oxazolidinones from phenylglycine by phase-transfer catalysis or with KOtBu as base are used to prepare optically active α-ethyl-α-phenylglycine.

PATENT

https://patents.google.com/patent/CN106866669A/en

⑴ Route A:

[0005] ⑵ Route B:

[0007] (3) Route C:

[0009] Scheme C, wherein the method further comprises synthesizing Via, namely:

Won] now, with respect to the other two routes, from the reaction step, time costs, material costs, product yield and product purity of view, comparing the current line C is respected, it is more suitable for production. But even so, there are still a number of route C the following questions:

[0012] [1], the synthesis of compound V, there is a slow reaction, and the reaction was not complete and so on;

[0013] [2], when Via a salt, the desired product is low chiral purity and yield to be improved;

[0014] [3], when VIII recrystallized grain size to be improved.

CLIP

Image result for rolapitant synthesis

References

1: Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M; Rolapitant Investigation Group. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg.
2011 Apr;112(4):804-12. Epub 2011 Mar 8. PubMed PMID: 21385988.

2. Reddy GK, Gralla RJ, Hesketh PJ. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support Cancer Ther. 2006 Apr 1;3(3):140-2. PubMed PMID: 18632487.

3. Drug Data Rep 2003, 25(8): 703

4. A multicenter, randomized, double blind, active-controlled study of the safety and efficacy of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (NCT01500226)
ClinicalTrials.gov Web Site 2012, February 06

5. Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting in subjects receiving highly emetogenic chemotherapy
48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 9077

6. Proposed international nonproprietary names (Prop. INN): List 97
WHO Drug Inf 2007, 21(2): 160

References

^ Jump up to:^a ^b “Varubi (rolapitant) Tablets, for Oral Use. Full Prescribing Information” (PDF). TESARO, Inc. 1000 Winter St., #3300, Waltham, MA 02451.
^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 59” (PDF). World Health Organization. p. 64. Retrieved 5 October 2016.
^ Duffy, R. A; Morgan, C; Naylor, R; Higgins, G. A; Varty, G. B; Lachowicz, J. E; Parker, E. M (2012). “Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets”. Pharmacol Biochem Behav. 102 (1): 95–100. doi:10.1016/j.pbb.2012.03.021. PMID 22497992.
^ Jordan, K; Jahn, F; Aapro, M (2015). “Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review”. Ann Oncol. 26 (6): 1081–90. doi:10.1093/annonc/mdv138. PMID 25755107.
^ Nasir, S. S; Schwartzberg, L. S (2016). “Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting”. Oncology. 30 (8): 750–62. PMID 27539626.
^ Rapoport, B; Schwartzberg, L; Chasen, M; Powers, D; Arora, S; Navari, R; Schnadig, I (2016). “Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy”. Eur J Cancer. 57: 23–30. doi:10.1016/j.ejca.2015.12.023. PMID 26851398.
^ Chasen, M. R; Rapoport, B. L (2016). “Rolapitant for the treatment of chemotherapy-induced nausea and vomiting: a review of the clinical evidence”. Future Oncol. 12 (6): 763–78. doi:10.2217/fon.16.11. PMID 26842387.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Varuby: EPAR – Product Information” (PDF). European Medicines Agency. 2017-05-31.
^ Jump up to:^a ^b FDA Professional Drug Information on Varubi. Accessed 2017-10-11.
^ Jump up to:^a ^b “Varuby: EPAR – Public assessment report” (PDF). European Medicines Agency. 2017-05-31.

Rolapitant
Clinical data

Pronunciation	/roʊˈlæpɪtænt/ roh-LAP-i-tant
Trade names	Varubi (US), Varuby (EU)
Synonyms	SCH 619734
AHFS/Drugs.com	varubi
License data	EU EMA: by INN
Routes of administration	By mouth (tablets)
ATC code	A04AD14 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	nearly 100%
Protein binding	99.8%
Metabolism	CYP3A4
Metabolites	C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life	169–183 hours
Excretion	Feces (52–89%), urine (9–20%)^[1]
Identifiers
IUPAC name [show]
CAS Number	552292-08-7
PubChem CID	10311306
IUPHAR/BPS	5749
DrugBank	DB09291
ChemSpider	8486772
UNII	NLE429IZUC
KEGG	D10742
ChEBI	CHEBI:90908
Chemical and physical data
Formula	C₂₅H₂₆F₆N₂O₂
Molar mass	500.476 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] FC(F)(F)c(c4)cc(C(F)(F)F)cc4C(C)OCC3(c2ccccc2)NCC1(CC3)NC(=O)CC1

/////////////ROLAPITANT, ロラピタント, FDA 2015, Schering-Plough, TESARO,

Tildrakizumab-asmn

June 1, 2018 8:14 am / Leave a comment

Heavy chain:
	QVQLVQSGAEVKKPGASVKVSCKASGYIFITYWMTWVRQAPGQGL
	EWMGQIFPASGSADYNEKFEGRVTMTTDTSTSTAYMELRSLRSDD
	TAVYYCARGGGGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
	GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
	LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC
	PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
	EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
	KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL
	YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	Light chain:
	DIQMTQSPSSLSASVGDRVTITCRTSENIYSYLAWYQQKPGKAPK
	LLIYNAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQH
	HYGIPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL
	LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
	LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Tildrakizumab-asmn

Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

CAS 1326244-10-3, BLA 761067

Tildrakizumab (SCH 900222/MK-3222)

ILUMYA; MK-3222; SCH-900222; SUNPG 1622; SUNPG 1622 I; SUNPG 1623 I; SUNPG 1623 II; SUNPG 1623 III; SUNPG 1623 IV; SUNPG1623; Tildrakizumab-asmn

DRUG BANK https://www.drugbank.ca/drugs/DB14004

Company Sun Pharmaceuticals

Approval Status FDA Approved March 2018 FOR Psoriasis, plaque

Treatments plaque psoriasis

Protein chemical formulaC₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆

Protein average weight144400.0 DaSequences

>Tildrakizumab Sequence
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEG
DEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSP
VGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVF
AHGAATLSP

Tildrakizumab
Monoclonal antibody
Type	?
Source	Humanized (from mouse)
Target	IL23
Clinical data
Trade names	Ilumya
Synonyms	Tildrakizumab-asmn
Routes of administration	Subcutaneous injection
ATC code	none
Identifiers
CAS Number	1326244-10-3
ChemSpider	none
KEGG	D10400
Chemical and physical data
Formula	C₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆
Molar mass	144.4 kg/mol

Originator Schering-Plough
Developer Almirall S.A.; Merck & Co; Schering-Plough; Sun Pharmaceutical Industries
Class Antipsoriatics; Monoclonal antibodies
Mechanism of Action Interleukin 23 inhibitors

Orphan Drug StatusNo
New Molecular EntityYes

Highest Development Phases

Registered Plaque psoriasis
Phase II Ankylosing spondylitis; Psoriatic arthritis
Discontinued Autoimmune disorders

Most Recent Events

21 Mar 2018 Registered for Plaque psoriasis in USA (SC) – First global approval
16 Feb 2018 Adverse events data from two phase III trials (reSURFACE 1 and 2) in chronic Plaque psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)
16 Feb 2018 Pharmacokinetics data from population PK model in healthy volunteers and patients with psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)

Ilumya (tildrakizumab-asmn) is an interleukin-23 antagonist.

Humanized monoclonal IgG1-kappa antibody against IL-23p19; produced in CHO cells
Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

Ilumya is specifically indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Ilumya is supplied as a solution for subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter.

Image result for tildrakizumab-asmn

Tildrakizumab (Ilumya) is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders.^[1] In the United States, it is approved for the treatment of moderate-to-severe plaque psoriasis.^[2]

Tildrakizumab was designed to block interleukin-23, a cytokine that plays an important role in managing the immune system and autoimmune disease. Originally developed by Schering-Plough, this drug is now part of Merck‘s clinical program, following that company’s acquisition of Schering-Plough.

Sun Pharmaceutical acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of U.S. $80 million. Upon product approval, Sun Pharmaceutical will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. ^[3]

Image result for tildrakizumab-asmn

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 patients. ^[4]^[5]

In 2016, tildrakizumab became the first IL-23p19 inhibitor to demonstrate positive results in Phase-3 clinical trials for the treatment of moderate-to-severe plaque psoriasis, further validating the importance of the role of IL-23 in psoriasis. Sun Pharma signed a licensing pact with Spain’s Almirall for marketing tildrakizumab in Europe ^[6]

In March 2018, it was approved by the Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis as an injection for subcutaneous use in the United States.^[2]

In 2014, Sun Pharma acquired worldwide rights to tildrakizumab from Merck; upon product approval, Sun Pharma is responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the product. In 2016, Almirall sublicensed the product for the development and marketing in Europe for the treatment of psoriasis.

References

Mechanism of Action

Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

FDA APPROVAL DATA

BLA 761067

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/761067Orig1s000REPLACEMENT_ltr.pdf

Please refer to your Biologics License Application (BLA) dated and received March 23, 2017 and your amendments, submitted under section 351(a) of the Public Health Service Act for ILUMYA (tildrakizumab-asmn) injection. We also refer to our approval letter dated March 20, 2018 which contained the following error: the Final Report Submission date was incorrectly listed for postmarketing requirement 3357-3. This replacement approval letter incorporates the correction of the error. The effective approval date will remain March 20, 2018, the date of the original approval letter.

LICENSING We have approved your BLA for ILUMYA (tildrakizumab-asmn) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, ILUMYA under your existing Department of Health and Human Services U.S. License No. 0002. ILUMYA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

MANUFACTURING LOCATIONS Under this license, you are approved to manufacture ILUMYA drug substance at . The final formulated drug product will be manufactured, filled, labeled, and packaged at MSD Ireland, Carlow, Ireland. You may label your product with the proprietary name, ILUMYA, and market it in 100 mg/1 mL single-dose prefilled syringe

DATING PERIOD The dating period for ILUMYA drug product shall be 36 months from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for your drug substance shall be months from the date of manufacture when stored at We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of your drug substance and drug product under 21 CFR 601.12.

PATENTS

WO 2014109927

PAPER

https://www.tandfonline.com/doi/full/10.4161/19420862.2015.988944

Tildrakizumab (SCH 900222/MK-3222) targets the p19 subunit of IL-23. The mAb was developed by Schering-Plough, which was acquired by Merck & Co. in 2009, and it was then licensed by Merck to Sun Pharmaceutical Industries Ltd in September 2014. Clinical development and regulatory activities will be conducted by Merck, but funded by Sun Pharma. As of October 2014, the safety and efficacy of tildrakizumab are being evaluated in 2 Phase 3 studies that are ongoing but not recruiting patients. Both studies include patients with moderate-to-severe chronic plaque psoriasis and subcutaneously administered drug. The 52-week Phase 3 NCT01729754 study has 4 arms (200 mg tildrakizumab; 100 mg tildrakizumab; 50 mg etanercept; and placebo only), and includes an optional long-term safety extension study. The estimated enrollment is 1050, and the estimated primary completion date is October 2019. The 64-week Phase 3 NCT01722331 study is evaluating the effects of either 200 mg or 100 mg tildrakizumab to placebo; it includes an optional long-term safety extension study. The estimated enrollment is 885, and the estimated primary completion date is June 2015.

Image result for tildrakizumab-asmn

Sun Pharma Announces U.S. FDA Approval of ILUMYA™ (tildrakizumab-asmn) for the Treatment of Moderate-to-Severe Plaque Psoriasis

NEWS PROVIDED BY

Sun Pharma

Mar 21, 2018, 09:04 ET

MUMBAI, India and PRINCETON, N.J., March 21, 2018 /PRNewswire/ — Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715, “Sun Pharma” and includes its subsidiaries and/or associate companies) today announced that the U.S. Food and Drug Administration (FDA) has approved ILUMYA™ (tildrakizumab-asmn) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. ILUMYA selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor leading to inhibition of the release of pro-inflammatory cytokines and chemokines. ILUMYA is administered at a dose of 100 mg by subcutaneous injection every 12 weeks, after the completion of initial doses at weeks 0 and 4. ILUMYA is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.

“With the approval of ILUMYA and our long-standing commitment in dermatology, we are focused on making a difference for people living with moderate-to-severe plaque psoriasis,” said Abhay Gandhi, President and Chief Executive Officer, North America, Sun Pharma. “We are committed to working with all relevant stakeholders to make ILUMYA available to appropriate people with plaque psoriasis.”

The FDA approval of ILUMYA for the treatment of adults with moderate-to-severe plaque psoriasis was supported by data from the pivotal Phase-3 reSURFACE clinical development program. In the two multicenter, randomized, double-blind, placebo-controlled trials (reSURFACE 1 and reSURFACE 2), 926 adult patients were treated with ILUMYA (N=616) or placebo (N=310). Results from these studies were published in The Lancet in July 2017, with primary endpoints presented at the 25th European Academy of Dermatology and Venereology (EADV) Congress.

Both Phase-3 studies met the primary efficacy endpoints, demonstrating significant clinical improvement with ILUMYA 100 mg compared to placebo when measured by at least 75 percent of skin clearance (Psoriasis Area Sensitivity Index or PASI 75) and Physician’s Global Assessment (PGA) score of “clear” or “minimal” at week 12 after two doses.

*Efficacy Primary Endpoint at Week 12 in Adults with Plaque Psoriasis (NRI)**
	reSURFACE 1 Study (NCT01722331)		reSURFACE 2 Study (NCT01729754)
	ILUMYA 100 mg n=309	Placebo n=154	ILUMYA 100 mg n=307	Placebo n=156
PGA of “clear” (0) or “minimal” (1)†	179 (58%)	11 (7%)	168 (55%)	7 (4%)
PASI 75†	197 (64%)	9 (6%)	188 (61%)	9 (6%)
PASI 90	107 (35%)	4 (3%)	119 (39%)	2 (1%)
PASI 100	43 (14%)	2 (1%)	38 (12%)	0 (0%)

* NRI = Non-Responder Imputation † Co-Primary Endpoints

Of the patients in the reSURFACE 1 study 74 percent (229 patients) achieved 75 percent skin clearance at week 28 after three doses, and 84 percent of patients who continued receiving ILUMYA 100 mg maintained PASI 75 at week 64 compared to 22 percent of patients who were re-randomized to placebo. In addition, 69 percent of the patients receiving ILUMYA 100 mg who had a PGA score of “clear” or “minimal” at week 28 maintained this response at week 64 compared to 14 percent of patients who were re-randomized to placebo.

Full Prescribing Information and Medication Guide for ILUMYA are attached:
PDF: https://mma.prnewswire.com/media/656994/Sun_Pharma_ILUMYA_US_Prescribing_Information.pdf
PDF: https://mma.prnewswire.com/media/656995/Sun_Pharma_ILUMYA_US_Medication_Guide.pdf

IMPORTANT SAFETY INFORMATION (continued)

Cases of angioedema and urticaria occurred in ILUMYA treated subjects in clinical trial. If a serious hypersensitivity reaction occurs, discontinue ILUMYA immediately and initiate appropriate therapy.

ILUMYA may increase the risk of infection. Treatment with ILUMYA should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to prescribing ILUMYA in patients with a chronic infection or a history of recurrent infection. Instruct patients receiving ILUMYA to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection, or is not responding to standard therapy, closely monitor and discontinue ILUMYA until the infection resolves.

Evaluate patients for TB infection prior to initiating treatment with ILUMYA. Initiate treatment of latent TB prior to administering ILUMYA. Monitor patients for signs and symptoms of active TB during and after ILUMYA treatment. Do not administer ILUMYA to patients with active TB infection.

Prior to initiating ILUMYA, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with ILUMYA.

The most common (≥1%) adverse reactions associated with ILUMYA include upper respiratory infections, injection site reactions, and diarrhea. Adverse reactions that occurred at rates less than 1% but greater than 0.1% in the ILUMYA group and at a higher rate than in the placebo group included dizziness and pain in extremity.

About the Phase-3 reSURFACE Trials
The Phase-3 studies (reSURFACE 1 and reSURFACE 2) were randomized, placebo-controlled, multicenter, three-part studies designed to demonstrate efficacy of ILUMYA in moderate-to-severe plaque psoriasis compared to placebo and comparative drug and to assess safety and tolerability. Part one of the studies randomized patients into three or four treatment arms, including ILUMYA 100 mg, ILUMYA 200 mg, placebo and etanercept (reSURFACE 2 only). After Week 12, patients on placebo were then re-randomized into ILUMYA 100 mg and 200 mg treatment arms to proceed into part two of the studies. Finally, in part three of the reSURFACE 1 study, responders (PASI ≥75) and partial responders (PASI ≥50 and PASI <75) to ILUMYA were re-randomized after Week 28 to continue the same treatment, a different dose of ILUMYA or placebo. Partial and non-responders to etanercept were treated with ILUMYA 200 mg in part three of the reSURFACE 2 study. Patients with guttate, erythrodermic, or pustular psoriasis were excluded.

About Psoriasis
Psoriasis is a chronic immune disease that appears on the skin. It is a non-contagious disorder that speeds the growth cycle of skin cells¹ and results in thick scaly areas of skin². The most common form, affecting about 80 to 90 percent of people living with psoriasis, is called plaque psoriasis³. It appears as red, raised areas of skin covered with flaky white scales, which may be itchy and painful and can crack and bleed². Many people with plaque psoriasis continue to struggle with the ongoing, persistent nature of this chronic disease.

About Sun Dermatology
Sun Dermatology (the branded dermatology division of a wholly owned subsidiary of Sun Pharma) is committed to expanding its dermatology portfolio to bring healthcare providers and patients around the world more treatment options and ongoing support for conditions like moderate-to-severe plaque psoriasis. Sun Pharma, along with its subsidiaries, is ranked fourth in dermatology prescription volume within the U.S. per IMS and is fifth largest specialty generic pharmaceutical company globally. In addition to ILUMYA, Sun Dermatology is comprised of several branded products indicated for the treatment of acne and actinic keratosis with a focus on other dermatologic conditions.

About Sun Pharma, Merck & Co., Inc., Kenilworth, NJ, USA, Agreement
Sun Pharmaceutical Industries Ltd.’s wholly owned subsidiary licensed worldwide rights to ILUMYA from a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, in 2014. Funded by a Sun Pharma subsidiary, Merck & Co., Inc., Kenilworth, NJ, USA was responsible for the completion of Phase-3 trials and submission of a Biologics License Application to the United States Food and Drug Administration (FDA), as well as manufacturing finished goods to support Sun Pharma’s initial product launch. Sun Pharma will be responsible for all post-approval regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. Sun Pharma will also be responsible for all regulatory, pharmacovigilance, post approval studies, manufacturing and commercialization of approved products for all non-U.S. markets. Merck & Co., Inc., Kenilworth, NJ, USA is eligible to receive milestone payments and royalties on sales of ILUMYA.

About Sun Pharma, Almirall S.A, Europe, Agreement
Sun Pharma and its wholly owned subsidiary and Almirall (Spanish Stock Exchange ticker: ALM) closed on July 2016 a licensing agreement on the development and commercialization of tildrakizumab-asmn for psoriasis in Europe. Under the terms of the licensing agreement, Almirall is able to lead European studies, and participate in larger Global clinical studies for plaque psoriasis indication subject to the terms of the Sun Pharma – Merck & Co., Inc., Kenilworth, NJ, USA agreements, as well as certain cost sharing agreements. Sun Pharma will be eligible to receive development and regulatory milestone payments and, additionally, sales milestone payments and royalties on net sales. Sun Pharma will continue to lead development of tildrakizumab-asmn for other indications, where Almirall will have right of first negotiation for certain indications in Europe. The agreement between Sun Pharma and Almirall remains subject to the exclusive licensing agreement between Sun Pharma and Merck & Co., Inc., Kenilworth, NJ, USA.

About Sun Pharmaceutical Industries Ltd. (CIN – L24230GJ1993PLC019050)
Sun Pharma is the world’s fifth largest specialty generic pharmaceutical company and India’s top pharmaceutical company. A vertically integrated business, economies of scale and an extremely skilled team enable us to deliver quality products in a timely manner at affordable prices. It provides high-quality, affordable medicines trusted by customers and patients in over 150 countries across the world. Sun Pharma’s global presence is supported by 41 manufacturing facilities spread across 6 continents, R&D centres across the globe and a multi-cultural workforce comprising over 50 nationalities. In India, the company enjoys leadership across 11 different classes of doctors with 30 brands featuring amongst top 300 pharmaceutical brands in India. Its footprint across emerging markets covers over 100 markets and 6 markets in Western Europe. Its Global Consumer Healthcare business is ranked amongst Top 10 across 3 global markets. Its API business footprint is strengthened through 14 world class API manufacturing facilities across the globe. Sun Pharma fosters excellence through innovation supported by strong R&D capabilities comprising about 2,000 scientists and R&D investments of approximately 8% of annual revenues. For further information, please visit www.sunpharma.com & follow us on Twitter @SunPharma_Live.

References
1. National Psoriasis Foundation. Facts about psoriasis. www.psoriasis.org/sites/default/files/for-media/MediaKit.pdf. Accessed on February 22, 2018.
2. National Psoriasis Foundation. About Psoriasis. www.psoriasis.org/about-psoriasis. Accessed on February 22, 2018.
3. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008 May; 58(5):826-50.

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