Top 5 Target	Count

Bacterial DNA gyrase	1
GABAA receptor(Gamma-aminobutyric acid A receptor)	1
NK1R(Neurokinin 1 receptor)	1
EGFR x FGFRs x PDGFR x SRC	1
κ opioid receptor(Kappa opioid receptor)	1

Drugs associated with Parke-Davis & Co. Ltd.

Norethindrone

Target

Mechanism

PR agonists

Active Org.

Fuji Pharma Co., Ltd. [+1]

Originator Org.-

Active Indication

Contraception [+8]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date20 Aug 1958

Chloramphenicol

Target

50S subunit

Mechanism

50S subunit inhibitors

Active Org.

Alfresa Pharma Corp. [+3]

Originator Org.

Parke-Davis & Co. Ltd.

Active Indication

Conjunctivitis, Bacterial [+2]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date01 Jan 1951

PD-117558

Target

Bacterial DNA gyrase

Mechanism

Bacterial DNA gyrase inhibitors

Active Org.

Parke-Davis & Co. Ltd.

Originator Org.

Parke-Davis & Co. Ltd.

Active Indication

Bacterial Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date-

Clinical Trials associated with Parke-Davis & Co. Ltd.

NCT00492037 / CompletedPhase 3

A 5-Day, Double-Blind, Placebo-Controlled Multicenter Study of Oral YM087 (CI-1025) to Assess Efficacy and Safety in Patients With Euvolemic or Hypervolemic Hyponatremia

Study of efficacy & safety of oral YM087 in subjects with euvolemic or hypervolemic hyponatremia

Start Date01 Jan 2000

Sponsor / Collaborator

Cumberland Pharmaceuticals, Inc.

[+1]

NCT00600106 / CompletedNot ApplicableIIT

WISE Ancillary Study Data Analyses: Efficacy of Hormone Replacement on Myocardial Ischemia in Postmenopausal Women With Normal/Minimal Coronary Artery Disease: Data Analysis

The goal of the main trial was to evaluate the effect of low dose hormone replacement therapy with 1 mg norethindrone/10mcg ethinyl estradiol in postmenopausal women with a history of chest discomfort, myocardial ischemia and no obstructive CAD. For the purposes of this study as a core lab coordinating center, the investigators will be performing P31 MRS core lab analyses; hormone core lab analyses; lipid core lab analyses; glucose, insulin and HOMA core lab analyses; exercise stress test/Holter monitor core lab analyses; brachial artery reactivity test core lab analyses; full study data analyses for manuscript preparation and the writing and submission and publication of manuscript.
The main trial duration: December 1999 - May 2003.
The ancillary data analysis project duration: April 2006 - March 2010.

Start Date01 Dec 1999

Sponsor / Collaborator

Cedars-Sinai Medical Center

[+6]

NCT00007670 / CompletedPhase 3IIT

CSP #428 - Treatment of Seizures in the Elderly Population

New onset epilepsy in the elderly occurs in 45,000-50,000 elderly patients each year. These patients are especially vulnerable to side effects from medications because of changes caused by the aging process and the fact that these patients often have many common diseases for which they are already receiving medications for so that the likelihood of drug interactions is increased. Two new drugs, gabapentin and lamotrigine, have recently been approved by the FDA as antiepileptic drugs. These drugs have demonstrated efficacy in the treatment of partial onset seizures, the most common seizures in the elderly. These new compounds also have favorable side effect profiles and infrequent drug-drug interactions and, therefore, would be expected to be well-tolerated in the elderly.

Start Date01 Jan 1998

Sponsor / Collaborator

US Department of Veterans Affairs (District of Columbia)

[+2]

100 Clinical Results associated with Parke-Davis & Co. Ltd.

0 Patents (Medical) associated with Parke-Davis & Co. Ltd.

Literatures (Medical) associated with Parke-Davis & Co. Ltd.

01 Jan 1971·Journal of the Chemical Society C: Organic

The preparation of derivatives of dibenz[b,d]oxepin

Author: Harrow, T. A. ; Harrison, Christine Elizabeth ; Williamson, William R. N.

Reaction of (2-biphenylyloxy)acetyl chloride with AlCl3 or reaction of the corresponding acid with polyphosphoric acid gave dibenz[b,d]-oxepin-7(6H)-one (I, R = O).Schmidt reaction of I (R = O) or Beckmann rearrangement of I (R = NOH) gave 6H-dibenz[e,g] [1,4] oxazocin-7(8H)-one (II).N-Substituted derivatives of II, prepared from alkyl halides and the N-sodio derivative, were reduced (LiAlH4) to the corresponding N-substituted dihydrodibenzoxazocines.Reactions of I (R = O) with MeMgI and PhMgBr gave the expected alcs. (I, R = OH, Me and OH, Ph resp.), and Reformatskii reaction of BrCH2CO2Et on I (R = O) and alk. hydrolysis gave I (R = OH,CH2CO2H).Reaction of I (R = O) with (EtO)2(EtCO2CH2O)PO followed by alk. hydrolysis gave a β,γ-unsaturated acid, whereas acid hydrolysis gave an α,β-unsaturated acid (I, R = CHCO2H).

01 Jan 1965·Journal of the Chemical Society (Resumed)

476. The synthesis of alkoxy-1,2,3,4-tetrahydromaphthalene derivatives. Part I. 2-Amino-, alkylamino-, and dialkylamino-derivatives

Author: Richards, K. E. ; Evans, D. ; Grey, T. F. ; Islip, P. J. ; Ames, D. E.

A series of the title compounds, e.g. I, via dialkoxynaphthalenes and II, has been prepared for pharmacol. testing.

01 Jan 1958·Journal of the Chemical Society (Resumed)

318. The synthesis of the v-triazolo[d]pyrimidine analogues of adenosine, inosine, guanosine, and xanthosine, and a new synthesis of guanosine

Author: Davoll, J.

cf. C.A. 46, 3959e.The title compounds and other glycosyl-v-triazolo[d]pyrimidine were synthesized from chloromercuri derivatives of appropriate triazolopyrimidines (I) prepared by modifications of standard methods, acetylated, and the AcO derivatives(II) converted into chloromercuri compounds(III) which were condensed with acylglycosyl halides as described for the corresponding purines (cf. Davoll and Lowy, C.A. 45, 10202d).AcOH (22 mL.) and 200 mL. aqueous 5,6-diamino-4-D-glucosylamino-2-methylthiopyrimidine, prepared according to Holland, et. al. (C.A. 43, 146c), from 6.5 g. 6-amino-4-D-glucosylamino-2-methylthiopyrimidine, were stirred with dropwise addition of 1.43 g. NaNO₂ in 20 mL. H₂O, the mixture was kept 2 h. at room temperature, the solution evaporated in vacuo below 40°, the residue acetylated with Ac₂O-C₅H₅N at room temperature, the product (3.64 g.) extracted with CHCl₃, the amorphous powder refluxed 2 h. in 250 mL. alc. containing Raney Ni (from 28 g. alloy), filtered hot and the filtrate and washings evaporated, the residue (1.77 g.) deacetylated with NH₃ in MeOH at 0°, and the product converted into 1.41 g. picrate, m. 201° (decomposition after 4 recrystallizations from H₂O).Treatment of the picrate with Dowex Number 1 anion exchange resin gave I (R = H, R¹ = NH₂, R² = β-D-glucopyranosyl) (Ia), m. 241° (decomposition) (H₂O), [α]²⁰_D -22° (c 1.0, H₂O).II in 10 volumes cold H₂O solubilized by the addition of 1 or 2 equivalents of N NaOH, the filtered solution treated with 1 mol HgCl₂ in hot alc. (8 mL./g. 20 volumes H₂O, and 1.5 parts by weight (of I) Hyflo Supercel, the mixture cooled and filtered, and the residue washed, dried, and powd. gave 80-90% III.In the reaction of III with tetra-O-acetylglucosyl bromide the procedure of D. and L. (loc. cit.) was followed; reactions using tri-O-benzoyl-D-ribofuranosyl chloride (IV) were carried out according to Kissman, et al. (C.A. 49, 8298e), except that the final extraction of the crude condensation product with Et₂O was omitted.The crude wet product from the nitrosation of 35 g. 4,6-diamino-2-mercaptopyrimidine refluxed 1 h. with stirring with 3 l. H₂O, 120 mL. NH₄OH (d. 0.88), and Raney Ni (from 180 g. alloy) and the mixture filtered hot, evaporated in vacuo to 1.2 l. and shaken with C, the hot filtrate treated with 75 cc. AcOH and stirred with dropwise addition of 13 g. NaNO₂ in 100 mL. H₂O gave 13.5 g. I (R = R² = H, R¹ = NH₂) (lb).Ib (2 g.) and 20 mL. Ac₂O refluxed 4 h. and the cooled mixture filtered, the residue washed with alc. and dried gave 2.06 g. acetamido compound, C₆H₆N₆O, m. 293-4° (50% EtOCH₂CH₂OH).The corresponding IIIb (9.05 g.) and 10 g. tetra-ο-acetyl-D-glucopyranosyl bromide gave 8.5 g. sirup, crystallized from 150 mL. alc. to give 0.5 g. needles, m. 270°, not giving a crystalline product on deacetylation with NH₃ in MeOH.The alc. filtrate evaporated and the residue deacetylated with NH₃ in MeOH at 0° gave 0.85 g. (?) 7-amino-1-β-D-glucopyranosyl-v-triazolo[d]pyrimidine (V) (R = H, R¹ = NH, R² = β-D-glucopyranosyl) (Va), C₁₀H₁₄N₆O₅, m. 250-1° (decomposition) (H₂O); picrate, m. 160° (effervescence of 1 mol alc. of crystallization) (50% alc.).Addition of picric acid to the filtrate from Va gave 1.53 g. Ia picrate, converted to Ia with UV absorption spectrum identical with that of the above synthetic material.IIIb (16.7 g.) condensed with 1.09 mol IV, the sirup (24.5 g.) deacetylated with NaOMe, the mixture neutralized with CO₂ and evaporated, the residue triturated with dry Et₂O and the dried, BzOMe-free material crystallized from 125 mL. H₂O and decolorized with C yielded 16% 8-azaadenosine (I, R = H, R¹ = NH, R² = 3-β-D-ribofuranosyl) (Ic), m. 218-19° (H₂O), [α]²²_D -79° (c 0.46, H₂O); picrate, m. 184° (decomposition) (H₂O).Addition of picric acid to the mother liquor from Ic gave 7.25 g. impure picrate, converted to amorphous material, λ 273 mμ (0.1N HCl), λ 287 mμ (0.1N NaOH).Ic (2 g.) and 5 g. NaNO₂ in 25 mL. hot H₂O cooled rapidly, the solution treated with 5 mL. AcOH, kept 1 h., diluted with 25 mL. H₂O, stored 18 h., treated with aqueous Pb(OAc)₂ and NH₄OH, and filtered, the Pb salt taken up in 20% AcOH, the solution saturated with H₂S, the filtered solution evaporated, and the residue (1.87 g.) repeatedly recrystallized (80% alc.) gave 1.38 g. 8-azainosine (I, R = H, R¹ = HO, R² = β-D-ribofuranosyl) (Id), C₉H₁₁N₅O₅, m. 199-200°, [α]²¹_D -54° (c 1.78, H₂O).NaNO₂ (4.85 g.) in 30 mL. H₂O added dropwise with stirring to 8.5 g. 2,4,6-triaminopyrimidine in 220 mL. 10% AcOH, the mixture kept 1 h., diluted with 115 mL. AcOH, and hydrogenated 1 h. with 5% Pd-C, the filtered solution treated dropwise with 4.85 g. NaNO₂ in 30 mL. H₂O with stirring and filtered, the product treated with C in hot dilute aqueous NH₄OH, and the hot filtrate acidified with AcOH gave 7.55 g.I (R = R¹ = NH, R² = H) (Ie).Ie (9.76 g.) refluxed 30 min. in 98 mL. Ac₂O, the cooled mixture filtered, the residue washed with alc., the triacetyl compound, m. 210° (decomposition), boiled with 200 mL. moist EtOC₂H₄OH and filtered and the residue washed with EtOH gave 9.94 g. diacetamido derivative, m. 280° (decomposition), converted to the chloromercuri compound (IIIe).IIIe (8 g.) and 1 mol IV condensed and the pale yellow glass (11.4 g.) deacylated with NaOMe yielded 42% (?) 5,7-diamino-β-D-ribofuranosyl-v-triazolo[d]pyrimidine(s) (VI), m. 127-50° (H₂O).PhCH₂MeNH (9 mL.) and 3 g. 2,4-diamino-6-chloropyrimidine refluxed 1 h., the cooled mixture extracted with 60 mL. boiling EtOAc, the extract washed with 5% AcOH, and the dried (Na₂SO₄) extract evaporated gave 2.15 g. 2,4-diamino-6-(N-methylbenzylamino)pyrimidine acetate, m. 146-8°, which, nitrosated in 20% AcOH, the product hydrogenated in 50% AcOH with 10% Pd-C, and the filtered solution treated with 1 mol aqueous NaNO₂ and filtered, gave I (R = R¹ = NH, R² = Me) (If), C₅H₇N₇, m. 294-5° (H₂O), insoluble in alkali.IIIe and IV condensed and the crude product (18.9 g.) deacylated with NH₃ in MeOH, treated with HNO₂ and deacylated with NaOMe gave 1.26 g. (?) V (R = NH₂, R¹ = HO, R² = β-D-ribofuranosyl) (Vb), C₉H₁₂N₆O₅, m. above 200° (decomposition), [α]²⁰_D -75° (c 0.9, H₂O), hydrolyzed 2 h. in boiling N HCl to give material with the spectrum of I (R = NH₂, R¹ = HO, R² = H).VI (0.45g.) refluxed 45 min. in 5 mL. Ac₂O and the solution evaporated, the residue treated as above also gave 24% Vb, identified by UV spectra in acid and alkali.2-Methylthio-9-β-D-ribofuranosyladenine (D. and L., loc. cit.) (0.5 g.) in 100 mL. 0.4N H₂SO₄ treated with 1.2 g. NaNO₂ and the mixture kept 18 h., neutralized with NH₄OH and evaporated to 15 mL. gave 0.46 g. 2-methylthio-9-β-D-ribofuranosylhypoxanthine, (VII), m. 246° (decomposition).VII (0.5 g.) in 4 mL. aqueous NH₄OH (d. 0.88) and 4 mL. alc. NH₃ (saturated at 0°) heated 18 h. at 130-2° in a sealed tube, the cooled mixture evaporated and the residue recrystallized (H₂O) 4 times with decolorizing C gave 0.12 g. authentic guanosine.NaNO₂ (0.69 g.) in a min. of H₂O added to 1.71 g. 4,5,6-triamino-2-methylthiopyrimidine in 55 mL. 10% AcOH and filtered, the precipitate treated with C in hot dilute aqueous NH₄OH, and the filtered solution acidified with AcOH gave 1.55 g. I (R = MeS, R¹ = NH, R² = H), m. 282° (decomposition), refluxed (1 g.) 2 h. in 5 mL. Ac₂O and the cooled mixture diluted with 10 mL. anhydrous Et₂O to give 1.06 g. crystalline diacetyl compound, m. 153-5°, transformed on standing in the open with loss of 1 Ac group to give 7-acetamido-5-methylthio-v-triazolo[d]pyrimidine (Ig), m. 215-17°, recrystallized (70% alc.) to give solvated needles, C₇H₈N₆OS.C₂H₆O, m. 219-220°, transformed to the corresponding chloromercuri compound (IIIg).IIIg (23 g.) and 1 mol IV condensed and the product (31 g.) deacylated with NaOMe, taken up in 175 mL. hot H₂O and treated with C, the solution kept 1.5 h. at room temperature and filtered gave 3.79 g.I (R = MeS, R¹ = NH₂, R² = β-D-ribofuranosyl) (Ih), m. 200-1° (H₂O).The filtrate kept 20 h. at 3° and filtered gave 2.8 g. (?) V (R = MeS, R¹ = NH₂, R² = β-D-ribofuranosyl) (Vc), m. 156-8° (H₂O).Treatment of Ih with Ac₂O-C₅H₅N at room temperature yielded 84% I (R = H, R¹ = NH₂, R² = tri-O-acetyl-β-D-ribofuranosyl), m. 152-3° (alc.), boiled (0.14 g.) 2 h. in 10 mL. alc. with 1 g. Raney Ni and the product deacetylated with NH₃ in MeOH to give 18 mg. Ic.Desulfurization of Vc gave an amorphous product producing gelatinous solutions in H₂O, λ 285 mμ (0.1N HCl), 292 mμ (0.1N NaOH).Ih (0.5 g.) in 100 mL. N HNO₃ treated 20 h. at room temperature with 1.2 g. NaNO₂ and the mixture filtered gave 0.43 g.I (R = MeS, R¹ = HO, R² = β-D-ribofuranosyl) (Ii), m. 181-3° (sintering above 178°) (H₂O).Ii (0.5 g.) aminated as above (preparation of guanosine) and the product isolated through the Pb salt yielded 8% 8-azaguanosine (I, R = NH, R¹ = HO, R² = β-D-ribofuranosyl) (Ij), C₉H₁₂N₆O₅, m. 250-2° (decomposition) (H₂O), hydrolyzed 2 h. with boiling N HCl to give a compound with the UV absorption spectrum of 5-amino-7-hydroxy-v-triazolo[d]pyrimidine, λ 250 mμ (0.1N HCl).Vc (0.5 g.) and 1.2 g. NaNO₂ in 12 mL. hot H₂O and the rapidly cooled solution treated with 1.2 mL. AcOH, the mixture kept 24 h. and the product isolated through the Pb salt yielded 56% (?) V (R = MeS, R¹ = HO, R¹ = β-D-ribofuranosyl) (Vd), m. 214-15°.I (R = NH₂, R¹ = HO, R² = H) (15.5 g.) refluxed 2 h. in 155 mL. Ac₂O and the cooled mixture filtered, the product washed with alc. and dried gave 23.2 g. diacetyl derivative, m. 219°.The corresponding chloromercuri compound (31 g.) condensed with 1.15 mol IV, the pale yellow gum (41.5 g.) refluxed 1 h. with NaOMe (from 2.5 g. Na in 400 mL. MeOH), the mixture evaporated, the residue in 500 mL. H₂O made just acidic with AcOH, boiled and treated with C, the filtered solution kept 18 h. at room temperature and filtered gave 7.33 g. material, recrystallized to give 6.28 g. (?) 5-amino-7-hydroxy-2-β-D-ribofuranosyl-v-triazolo[d]pyrimidine (VIII), m. 230-5° (sintering) (H₂O), [α]²⁰_D -79° (c 0.77, 0.1N NaOH).The filtrate evaporated to 200 mL. and cleared by heat, kept 5 h. and filtered yielded 4.62 g. material recrystallized (H₂O) to give 3.9 g.Ij, [α]²¹_D -97° (c 1.0, 0.1N NaOH).The mother liquors evaporated to 50 mL. gave 4.13 g. material containing 85% Ij, deaminated to yield pure I (R = R¹ = HO, R² = β-D-ribofuranosyl) (I-k).Ij (0.3 g.) and 1 g. Ba(NO₃)₂.H₂O in 4 mL. hot H₂O and the rapidly cooled solution treated with 1 mL. AcOH, kept 5 h. and treated with 8.06 mL. N H₂SO₄, the filtered solution evaporated in vacuo below 15° and the residue crystallized (4 mL. 5:2 alc.-H₂O) gave 0.14 g. Ik, 8-azaxanthosine, m. 198-9° (decomposition), [α]²⁰_D -103° (c 1.02, 0.1N NaOH).The spectral characteristics of the products were tabulated [pyrimidine, λ_maximum in mμ (10^-3 ε) in HCl (normality indicated), at pH 6.8, and in NaOH (normality indicated) recorded]: Va, 244, 286 (5.3, 11.6, 0.1N), 246, 299 (5.5, 10.3), 245, 299 (5.3, 9.8, 0.1N); Ia, 263 (12.5, 0.1N), 280 (11.7), 280 (11.2, 0.1N); Ic, 260 (12.4, 0.1N), 279 (12.0), 278 (12.4, 0.1N); Id, 255 (9.4, 0.1N), 256 (8.8), 277 (10.5, 0.1N); VI, 260, 286 (11.5, 10.0, 0.1N), 222, 291 (21.7, 7.2), 329 (7.4, 0.1N); If, 254, 284 (9.1, 6.7, 0.1N), 258, 287 (5.1, 8.8), 259, 287 (5.1, 8.8, 0.1N); Vc, 230, 285, 303 (12.3, 13.3, 12.6, 0.05N), 223, 248, 279, 308 (15.9, 13.3, 10.5, 9.8), 248, 279, 310 (14.4, 10.3, 10.1, 0.05N); Ih, 245, 280 (13.7, 14.7, 0.05N), 248, 289 (19.4, 13.5), 247, 289 (18.9, 12.9, 0.05N); Vd, 222, 238, 287 (14.0, 14.8, 9.9, 0.05N), 219, 242, 288 (15.0, 14.3, 9.8), 244, 276, 300 (15.0, 9.8, 10.8, 0.05N); Ii, 232, 273 (9.5, 18.0, 0.05N), 242, 276 (12.5, 15.1), 242, 283 (16.8, 14.8, 0.05N); Vb, 285 (6.3, 0.01N), 238, 297 (8.4, 7.1), 254, 256, 304 (5.6, 5.6, 8.8, 0.03N); Ij, 255, 269 (13.6, 10.3, 0.01N), 256, 275 (13.7, 9.5), 221, 279 (23.0, 11.6, 0.03N); Ik, 240, 256 (5.9, 9.5, 0.1N), 252, 277 (9.7, 8.8), 251, 280 (7.1, 9.5, 0.1N); VII, 265 (15.1, 0.05N), 262 (14.8), 225, 271 (19.2, 14.8, 0.05N).

News (Medical) associated with Parke-Davis & Co. Ltd.

06 Jun 2024

·www.biospace.com

Sermonix Pharmaceuticals Announces Chinese Approval of Investigational New Drug Application for Lasofoxifene

IND approval in China allows Shanghai Henlius Biotech, Sermonix’s Chinese development partner for oral lasofoxifene, to enroll ELAINE-3 trial patients in China Under strategic collaboration agreement signed in January, Henlius received exclusive rights from Sermonix to develop, manufacture and commercialize oral lasofoxifene in China Sermonix and Henlius will engage with PMDA and collaborate on expedited co-development of oral lasofoxifene in Japan COLUMBUS, Ohio, June 06, 2024 (GLOBE NEWSWIRE) -- Sermonix Pharmaceuticals LLC, a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers (mBC), today announced that China’s National Medical Products Administration (NMPA) approved the investigational new drug application (IND) for oral lasofoxifene (HLX78 in China) submitted with the assistance of Chinese development partner Shanghai Henlius Biotech, Inc. (2696.HK). The IND approval allows Henlius to join the ongoing global registrational ELAINE-3 trial with responsibility in China. ELAINE-3 (NCT05696626), the third Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) trial, is assessing the efficacy of oral lasofoxifene and Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib (Verzenio®) compared to fulvestrant and abemaciclib in 400 pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation. This month, Henlius expanded its license from Sermonix to add additional Asia territories for upfront, milestone and royalty payments. The agreement also allows Henlius to share with Sermonix expedited co-development of oral lasofoxifene in Japan. Sermonix has completed a Phase 1 Japanese PK study and, together with Henlius, will begin engagement with the Pharmaceuticals and Medical Devices Agency (PMDA) to address a regulatory path to study lasofoxifene in Japan, which is an important region for expanded global access to lasofoxifene investigation. “With active ELAINE-3 enrollment already underway in the U.S., Canada, EU and Israel, we are pleased to announce that Henlius, our Chinese development partner for oral lasofoxifene, received approval for its investigational new drug application,” said Dr. David Portman, Sermonix founder and chief executive officer. “This milestone clears Henlius to enroll patients in ELAINE-3 in China, therefore further diversifying our patient population and potentially helping more people to better confront this terrible disease.” “The collaboration between Henlius and Sermonix started in January 2024,” said Ms. Ping Cao, Henlius chief business development officer and SVP of business development. “In mere months from agreement to amendment, our unified dedication shines, turning swift collaboration and full-hearted implementation into tangible success – as underscored by our product's IND approval in China." Oral lasofoxifene is an investigational novel targeted endocrine therapy in clinical development that has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. In two completed Phase 2 clinical studies (ELAINE-1 and ELAINE-2), lasofoxifene demonstrated anti-tumor activity against tumors with ESR1 mutations as a monotherapy and in combination with abemaciclib, a CDK4/6 inhibitor. Lasofoxifene’s bioavailability and potent activity in mutations of the estrogen receptor, in addition to its potential to improve sexual and urogenital health with a well-tolerated profile, could hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, and, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer. Breast cancer is the second most diagnosed cancer in the world, according to GLOBOCAN 2022. There were around 2.3 million new cases of breast cancer in 2022 globally, including more than 357,000 in China.1 ER+ breast cancer comprises 60-70% of all breast cancers.2 Endocrine therapy remains the mainstay treatment for ER+ breast cancer and the most widely used class of aromatase inhibitor (AI) has been recommended by the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines to be the adjuvant and first-line standard of care for patients with ER+/HER2- breast cancer.3,4 However, almost all patients treated with AIs in the advanced setting develop resistance,5 with ESR1 mutations being one of the most prevalent alterations, present in up to 40% of patients and a significant mechanism of resistance to endocrine therapy.6 Currently, there are limited treatment options for ER+/HER2- breast cancer with ESR1 mutations, and thus a large clinical need exists. [1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and MortalityWorldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. [2] Ignatiadis M, Sotiriou C. Luminal breast cancer: from biology to treatment[J]. Nat Rev Clin Oncol, 2013, 10(9): 494-506. doi: 10.1038/nrclinonc.2013.124. [3] Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines 2023 [4] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2023 [5] Rozeboom B, Dey N, De P. ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future. Am J Cancer Res. 2019;9(12):2821-2831. Published 2019 Dec 1. [6] Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579. Published 2016 May 13. doi:10.1038/ncomms11579 About Sermonix Sermonix Pharmaceuticals Inc. is a privately held biopharmaceutical company focused on the development of female-specific oncology products and is currently undertaking a Phase 3 clinical study of lasofoxifene, its lead investigational drug. The Sermonix management team, led by founder Dr. David Portman, has significant experience in all stages of the drug development, regulatory and commercialization processes. Paul Plourde, M.D., vice president of oncology clinical development, has many decades of experience at AstraZeneca in the breast cancer drug development arena. Barry Komm, Ph.D., chief scientific officer, is recognized for his expertise in nuclear receptor biology. Miriam Portman, M.D., is co-founder and chief operating officer, with expertise in clinical trial conduct and patient recruitment. Elizabeth Attias, M.M.Sc., Sc.D., chief strategy and development officer, has extensive experience in pharmaceutical drug commercialization. Simon Jenkins, Ph.D., vice president of operations, has over 30 years of experience in global drug development leadership. Sermonix non-executive chairman of the board is Anthony Wild, Ph.D., former president of both Parke-Davis Pharmaceuticals and Warner-Lambert’s Pharmaceutical Division. To learn more about Sermonix, visit SermonixPharma.com. To learn more about the ELAINE studies, visit DiscoverElaine.com. About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 5 products have been launched in China, 3 have been approved for marketing in overseas markets, 23 indications are approved worldwide, and 3 marketing applications have been accepted for review in China and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP. Sermonix Contact: Elizabeth Attias, Sc.D. Chief Strategy and Development Officer EAttias@sermonixpharma.com (973) 723-7832

Phase 2License out/inPhase 1Phase 3Drug Approval

30 May 2024

·www.biospace.com

Sermonix Pharmaceuticals to Present Poster on ELAINE-3 Trial in Progress at ASCO 2024

COLUMBUS, Ohio, May 30, 2024 (GLOBE NEWSWIRE) --Sermonix Pharmaceuticals LLC, a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers (mBC), today announced it will present a poster updating the progress of its Phase 3 ELAINE-3 clinical trial at the annual meeting of the American Society of Clinical Oncology (ASCO). ASCO 2024 will be held May 31-June 4, 2024, at McCormick Place in Chicago. Poster Details: Title: Open-label, randomized, multicenter, phase 3, ELAINE-3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation. Abstract Number: TPS1127 Poster Board Number: 101b Session Date/Time: June 2, 2024, 9 a.m.-noon CDT A global registrational study, the third Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) trial is assessing the efficacy of oral lasofoxifene and Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib (Verzenio®) compared to fulvestrant and abemaciclib in 400 pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation. “Sermonix looks forward to updating our peers at ASCO 2024 about the progress of ELAINE-3, which is actively enrolling in the U.S., Canada, Europe and Israel,” said Dr. David Portman, Sermonix founder and chief executive officer. “In previous trials, lasofoxifene demonstrated compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations and potential benefit on quality of life with respect to vaginal and sexual health. We are excited to gain a greater understand of lasofoxifene’s potential as ELAINE-3 progresses, and hopefully bring it one important step closer to patients.” About Sermonix Sermonix Pharmaceuticals Inc. is a privately held biopharmaceutical company focused on the development of female-specific oncology products and is currently undertaking a Phase 3 clinical study of lasofoxifene, its lead investigational drug. The Sermonix management team, led by founder Dr. David Portman, has significant experience in all stages of the drug development, regulatory and commercialization processes. Paul Plourde, M.D., vice president of oncology clinical development, has many decades of experience at AstraZeneca in the breast cancer drug development arena. Barry Komm, Ph.D., chief scientific officer, is recognized for his expertise in nuclear receptor biology. Miriam Portman, M.D., is co-founder and chief operating officer, with expertise in clinical trial conduct and patient recruitment. Elizabeth Attias, M.M.Sc., Sc.D., chief strategy and development officer, has extensive experience in pharmaceutical drug commercialization. Simon Jenkins, Ph.D., vice president of operations, has over 30 years of experience in global drug development leadership. Sermonix non-executive chairman of the board is Anthony Wild, Ph.D., former president of both Parke-Davis Pharmaceuticals and Warner-Lambert’s Pharmaceutical Division. Learn more at SermonixPharma.com. Sermonix Contact: Elizabeth Attias, Sc.D. Chief Strategy and Development Officer EAttias@sermonixpharma.com (973) 723-7832

Phase 3ASCO

06 May 2024

·www.biospace.com

Opinion: Can Ketamine Be Safely Used at Home?

Pictured: Collage of woman on bed with ketamine pills/Taylor Tieden for BioSpace The week before Easter 2024, many of the world’s leading ketamine researchers gathered at the annual conference for ketamine and related compounds at the Blavatnik School of Government in Oxford. The first day ended with a debate about the suitability of at-home administration of ketamine for depression, preceded and followed by a vote from the audience. The vote before the debate was slightly opposed to using ketamine as a treatment for depression to be taken at home. However, after the exchange of expert opinions, the subsequent vote was slightly in favor. Though this apparent swing in the vote may reflect a minor change, the fact that the debate took place is itself noteworthy. It shows that the ketamine scientific community is actively working on how to ensure that the profound and fast-acting antidepressant properties of ketamine can benefit patients while its risks are mitigated. Depression is a growing health concern, affecting 320 million people worldwide, and it is expected to be the leading global cause of disease burden by 2030. Many depressed individuals do not respond adequately to current treatments, and about a third remain treatment-resistant after multiple treatment attempts. The emergence of ketamine-based medications has sparked hope for people with treatment-resistant depression because of the rapid onset of robust efficacy. However, that efficacy has so far generally occurred together with characteristic side effects such as dissociative psychological experiences and changes in heart rate and blood pressure. This has, in turn, prompted regulators to demand that the only approved ketamine-based medication for depression be taken under adequate medical supervision, effectively limiting its use. Ketabon, a Munich-based pharmaceutical company where I work as chief medical officer, is working to develop a medication that harnesses ketamine’s antidepressant effects without the safety issues that currently prohibit its at-home use. A Unique Mechanism To understand where the ketamine field stands today, it is of interest to look at the history of this groundbreaking medication. Calvin Stevens, a scientist at Parke-Davis Laboratories, synthesized the compound in 1962 while searching for new analgesics. Initially known as CI-581, ketamine quickly caught the attention of researchers, including Edward Domino, a pharmacologist at the University of Michigan who made a fortuitous observation: ketamine induced a unique dissociative state in human subjects, distinct from the experience under traditional anesthetics. This observation laid the groundwork for subsequent investigations into ketamine’s mechanism of action. Employing a combination of animal studies and pharmacological assays, Domino and his colleagues uncovered compelling evidence implicating the N-methyl-D-aspartate (NMDA) receptor—then an emerging player in the field of neuroscience—as the primary target of ketamine’s action. By antagonizing this receptor, ketamine disrupted glutamatergic neurotransmission, leading to its characteristic dissociative and anesthetic effects. One of the most significant advantages of ketamine is its ability to induce anesthesia rapidly and reliably, making it particularly well-suited for use in emergency settings or during procedures where rapid onset is essential. Additionally, it induces minimal respiratory depression compared with older anesthetics. However, ketamine is not without its limitations and potential drawbacks. Hallucinations, delirium and emergence phenomena can occur, particularly at higher doses or in susceptible individuals. Furthermore, concerns have been raised regarding its abuse potential and the development of tolerance and dependence with chronic use. When ketamine was used primarily in controlled settings as an anesthetic, the risk of diversion could be managed. The first inklings of ketamine’s abuse potential emerged in the late 1970s, as reports began to surface of individuals seeking out the drug for recreational purposes. Ketamine’s unique psychoactive effects captivated certain segments of the population, particularly within the burgeoning rave and club scene. From Anesthetic to Antidepressant While ketamine’s psychoactive effects raised the potential for abuse, some saw in them the potential for beneficial uses beyond anesthesia. In the late 1990s, intrigued by reports of ketamine’s rapid and robust impact on mood in patients undergoing anesthesia, John Krystal and his colleagues at Yale University embarked on a series of groundbreaking studies to explore its potential as an antidepressant. Their efforts bore fruit in 2000, when they published the first clinical trial demonstrating that a single sub-anesthetic dose of ketamine could produce rapid and sustained antidepressant effects in individuals with treatment-resistant depression. Subsequent research confirmed and expanded upon these findings, suggesting that ketamine’s antidepressant action was mediated by its ability to modulate the glutamatergic system in the brain, particularly through its antagonism of the NMDA receptor. Until that time, most efficacious antidepressants were acting by modulation of monoamine neurotransmission, particularly serotonin and noradrenaline signaling. Importantly, clinically relevant improvement could be seen within days of beginning ketamine treatment, rather than after several weeks as with standard antidepressants. Encouraged by these results, academic researchers and pharmaceutical companies raced to develop ketamine-based treatments for depression, paving the way for a diverse array of formulations and delivery methods, with intravenous infusion being frequently used. Among the most notable innovations was the development of Johnson & Johnson’s intranasal spray of esketamine, the S-enantiomer of ketamine, approved in 2019 and marketed under the brand name Spravato. It offers several advantages over traditional antidepressant medications, including a rapid onset of action and the potential to provide relief for individuals who have not responded to conventional therapies. But Spravato, too, is not without its limitations and caveats, including acute side effects such as dissociation and sedation, as well as the potential for abuse and misuse. The latter prompted regulatory agencies to impose strict risk mitigation strategies, including the requirement for administration under the supervision of a healthcare provider in a certified healthcare setting. Nevertheless, the introduction of Spravato represents a significant milestone in the treatment of depression. Several attempts have been made to strike a balance between efficacy benefits and tolerability issues with ketamine and related compounds and to safeguard against unintended use. Strict rules regarding who should administer the medication, where it can be administered and how patients must be supervised after each treatment, as in the case of Spravato, has been one approach. This has, however, limited accessibility to one of the most important antidepressant treatments. Abuse-deterrent formulations, use of small pack sizes and certification of pharmacies are examples of other approaches aiming to ensure the safe use of ketamine-based antidepressants. A fundamentally different approach is being pursued by Ketabon, where we are developing KET01, an oral prolonged-release form of ketamine administered as a tablet. Because of the slow uptake of ketamine from the gut and the extensive metabolism of ketamine in the liver, the amount of ketamine that reaches the general circulation is much lower than what is seen with ketamine-based medications administered intravenously, intranasally or with immediate-release tablets. The resulting low concentration of circulating ketamine is not sufficient to elicit characteristic side effects that are most likely mediated via the NMDA receptor, such as dissociation, sedation and blood pressure increase. However, due to the extensive metabolism of ketamine, relatively high concentrations of metabolites like norketamine and hydroxynorketamine are found in the circulation after dosing with KET01. These metabolites have shown antidepressant-like properties in animal models. Clinical trial data presented by Ketabon at recent meetings show a rapid improvement in depressive symptoms among patients with treatment-resistant depression receiving KET01, with maintenance of the improvement during the three-week treatment and four-week follow-up periods. These efficacy signals were not associated with increases in dissociation, heart rate or blood pressure. The researchers at Ketabon hypothesize that the antidepressant efficacy of KET01 is driven by ketamine metabolites, while the minimal dissociation can be attributed to the low levels of circulating ketamine. The emerging data with KET01 suggest that it is indeed possible to achieve rapid improvement in depression without the characteristic side effects of ketamine-based medications. This raises the potential for broader and safe use of a ketamine-based medication for depression, with an improved tolerability profile. If this treatment is eventually approved, it will be interesting to see how its availability would affect the results of a vote regarding home use of ketamine like the one recently held at Oxford. Hans Eriksson, MD, PhD, MBA, is chief medical officer at Ketabon and HMNC Brain Health in Munich. Follow him on LinkedIn or learn more about his work at and .

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