9/25/18 Vulva LA Tak due 1-15-16 Vulvar Talk LA January 2016.pptx - - PDF document

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9/25/18 Vulva LA Tak due 1-15-16 Vulvar Talk LA January 2016.pptx - - PDF document

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REED 9/25/18 Vulva LA Tak due 1-15-16 Vulvar Talk LA January 2016.pptx 1-11-2016 UW MEDICINE NAMS 2018 DISCLOSURES RECENT ADVANCES IN THE TREATMENT Disclosures: Royalties from online UpToDate, OF VASOMOTOR SYMPTOMS Scientific

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UW MEDICINE │ NAMS 2018

Susan D Reed, MD, MPH

Professor and Vice Chair Department of Obstetrics and Gynecology Program Director, Women’s Reproductive Health Research Center University of Washington, Seattle

RECENT ADVANCES IN THE TREATMENT OF VASOMOTOR SYMPTOMS KNDy May Be the New Sweet Spot

Istockphoto.com

Disclosures:

  • Royalties from online UpToDate,

Scientific American, and ACP Smart Medicine

  • Research funding from NIH, Bayer
  • No COI

Trade Names: Every attempt made to present in a nonbiased fashion Definitions:

  • K = Kispeptin
  • N = Neurokinin B
  • Dy = dynorphin
  • PRKA = peripherally restricted

kappa agonist

  • NK3R = neurokinin 3 receptor
  • NK1R = neurokinin 1 receptor

DISCLOSURES

LEARNING OBJECTIVES

After this education, learners should be able to: Describe the rationale for targeting the KNDy neuron complex for new therapeutic interventions for menopausal symptoms Understand potential side effects from KNDy neuron therapeutics Describe what is known about drugs in the pipeline that target KNDy

KNDY NEURONS SECRETE NEUROPEPTIDES

Kisspeptin: G-protein coupled receptor ligand neuropeptide (gene kiss1) Neurokinin B: endogenous peptide ligand that belongs to the family of tachykinin peptides (gene TAC) highest affinity NK3R Dynorphin: kappa opiod KNDy neurons are co-localized with > 95% of ER, PR, AR in arcuate nucleus

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WORKING HYPOTHESIS

KNDy Neuron Arcuate Nucleus KNDy Neuron

Thermoregulatory Centers (MnPO) WSN Peripheral Effectors

Hyper-activation of KNDy neurons induces Hot Flashes

Hot Flashes

KNDy neurons are interconnected KNDY NEURON PULSE GENERATOR

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KNDy Neuron Arcuate Nucleus KNDy Neuron KNDy Neuron

KNDy neurons are interconnected NKB activates KNDY NEURON PULSE GENERATOR

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KNDy Neuron Arcuate Nucleus KNDy Neuron KNDy Neuron NKB

NKB

KNDy neurons are interconnected DYN inactivates KNDY NEURON PULSE GENERATOR

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KNDy Neuron Arcuate Nucleus KNDy Neuron KNDy Neuron

DYN DYN

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SILENCING KNDY NEURONS

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Blocking the NK3R with NK3R - antagonist reduces KNDy Activity Stimulating the KOR receptor with KOR agonist increases the impact of the Dynorphin KNDy Inactivation pathway

OR

NK3R

NKB Activation

NK3R NK3R- ANT

Activation

KOR

DYN NKB Activation

KOR

Activation

KOR-A

CLINICAL APPLICATIONS OF KNDY NEURON MANIPULATIONS

NKB agonists result in HF pre-MP (Jayasena, 2015) NKB antagonists suppress HF PMP (Prague, 2017) Genetic variations in the gene that encodes NKB are associated with variations in VMS frequency (Crandall 2017) Kappa antagonists ↑ LH pulsatility rats (Nakahara, 2013; Mosari,

2013)

Kappa agonists ↓ LH pulsatility and ↓ HF

(Oakley, 2015)

KNDY HOT FLASH RX PIPELINE

NK3R antagonists

– MLE 4901 – ESN364 Dual NK1R/NK3R antagonist – NT-814 PRKA (peripherally restricted kappa agonists)

HISTORY NK3R ANTAGONIST DRUGS

Osanetant SR-142, 801, NK3R antagonist, nonpeptide developed for schizophrenia and drug addiction ( blocked effects of cocaine in anima models) Emonds-Alt X. SR 142801,

the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sciences1995;56 (1): PL27–32.

Pavinetant MLE 4901 NK3R antagonist neuropeptide developed initially for schizophrenia, then HF, PCOS Talnetant SB-223,412 developed for schizophrenia and irritable bowel syndrome

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NK3R ANTAGONIST STRUCTURES

Osanetant SR-142, 801 Pavinetant MLE 4901 Fezolinetant ESN364 (HF) NT-814 (HF)

MLE 4901, PAVINETANT

Oral twice daily selective NK3R antagonist developed for schizophrenia, hot flashes (NCT02668185), PCO November 2017

Discontinued - Phase-II for Hot flashes in United Kingdom and Phase-II for Polycystic ovary syndrome in USA, Germany, United Kingdom Phase II trial for Hot flashes in United Kingdom showed the clinical risks exceeded benefits Abnormal liver function Plan to reformulate and reintroduce ~ 3 yr http://adisinsight.springer.com/drugs/800038259

MLE 4901, PAVINETANT

Prague J, Lancet 2017

Phase 2a study postmenopausal women

Frequency, severity, bother, interference MLE 4901, PAVINETANT

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Prague J, Menopause 2018

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ESN364, FEZOLINETANT

  • Selective NK3R antagonist
  • Oral twice daily
  • Phase 1, 2a trials for menopause
  • Phase 2a trials PCOS
  • Phase 2 trials uterine fibroids

Fraser G. J Clin Endocrinol Metab 2016 Fraser G. Endocrinol 2015 https://bciq.biocentury.com/products/fezolinetant

ESN364, FEZOLINETANT

Phase 1 studies healthy men and women

RCT 6:2 blinded, N=64 men single ascending dose

  • 3, 6, 12, 23, 46, 90, 180 mg

RCT 6:2, N=24 men, 10 days

  • repeat dose 20, 60, 180

RCT 6:2, N=24 women, 21 days

  • repeat dose 20, 60, 180

Findings

  • Rapid absorption (tmax 3-4 hours repeat dosing)
  • Linear PK (no accumulation on repeat dosing)
  • Short half life (4.4-6.3 hr in women, repeat dosing)
  • Dose response effect on reproductive hormones (LH, E2, P, T)
  • ↓endometrial thickening, delayed/impeded ovulation,

prolonged cycle duration

Fraser G. J Clin Endocrinol Metab 2016

ESN364, FEZOLINETANT

Phase 2 studies postmenopausal women

Phase 2a, 12 week RCT, N=80

  • moderate-severe HF
  • 90 mg bid

Findings

  • LH ↓ 50% (vs 16%), p <0.001
  • VMS frequency ↓93% (vs 54%), p <0.001
  • VMS severity ↓ 94% (vs 46%), p <0.001

Safety no SAEs, AEs similar between groups Phase 2b, 12- week RCT 1:6, N=352, NCT03192176 , 51 sites

  • 8 cohorts: Plcbo vs qd (4 doses) vs bid (4 doses)
  • dose range 30 - 180 mg/d
  • ONGOING, anticipate completion August 2019

Fraser G. ENDOABSTRACT 2017 Clinicaltrials.gov

ESN364, FEZOLINETANT

Sleep

Phase 2a 12 week RCT, N=80

  • moderate-severe HF
  • 90 mg bid

Findings

  • sleep improved ESN364 (vs placebo) p<0.001

Weight loss

Cynomolgus monkeys, N=12, 12 weeks

  • RCT
  • dose range 50 mg/kg/d vs vehicle control

Findings

  • ESN364 1% ↑ total body weight (vs 12% ↑ control)

Fraser G. ENDOABSTRACTS 2017 .

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EFFICACY ON HOT FLASH FREQUENCY ESN364, FEZOLINETANT

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Fraser G. ENDOABSTRACT 2017 With permission

EFFICACY ON HOT FLASH SEVERITY ESN364, FEZOLINETANT

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6 0 % ¯ 1 2 % ¯ 7 0 % ¯ 2 3 % ¯ * * * * * * * *

Fraser G. ENDOABSTRACT 2017 With permission

NT-814 NK1R, NK3R ANTAGONIST

  • Selective NK1R, NK3R antagonist
  • Oral once daily
  • Patent for “sex hormone dependent diseases”
  • Phase 1, 2a trials for menopause
  • Phase 2a trials PCOS

https://clinicaltrials.gov/ct2/show/NCT02865538

NT-814 NK1R, NK3R ANTAGONIST

Phase 1 study healthy men

Single blind, RCT, N=14 Doses: 10, 30, 60, 120, 160, 160-250 mg Findings

  • long t1/2 ~ 15 hr
  • rapid absorption at doses < 60 mg, ~ 1 hr
  • doses > 120 mg, t max ~ 4-5 hours
  • NK1R occupancy, EC50 0.875 ng/mL
  • NK3R occupancy, EC50 8.75 ng/mL

Safety: Increase somnolence, headache

GSK1144814 compound https://www.gsk-clinicalstudyregister.com

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NT-814 NK1R, NK3R ANTAGONIST

Phase 1 study healthy men and women

Open label, 3-way cross over, N=16 Dose 100 mg, 200 mg, placebo (with food) Findings

  • long t 1/2 ~ 26 hr
  • rapid absorption, t max ~ 1 hr, both doses

Safety (42 doses across groups)

9/42 somnolence (21%) vs 0/12 placebo 9/42 headache (21%) vs 5/12 placebo 2/42 dizziness (5%) vs 0/12 placebo

GSK1144814 compound https://www.gsk-clinicalstudyregister.com

NT-814

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https://clinicaltrials.gov/ct2/show/NCT02865538

Phase 2a study postmenopausal women Double blind RCT 14 days, N=80 Doses: 20 subjects each, placebo vs 50, 100, 150 and 200 mg Primary outcome: pharmacokinetics Secondary outcome: VMS, LH serum concentration

  • 9
  • 8
  • 7
  • 6
  • 5
  • 4
  • 3
  • 2
  • 1

Placebo 50 mg 100 mg 150 mg 300 mg

Median Reduction in HF Frequency in Week 2 – All Doses * *

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

  • 8 -7 -6 -5 -4 -3 -2 -1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean (+/- SE) Daily Frequemcy Day Placebo 150mg

NT-814, DAYTIME HOT FLASH FREQUENCY

BASELINE

Placebo N=18

WEEK 1 WEEK 2

150 mg N=15

Number of moderate and severe day time hot flashes recorded in a diary in the evening

* p<0.05 ** p<0.01 Wilcoxon rank-sum test

  • 37%
  • 84%

Anderson R, With from Permission KaNDY Therapeutics

PERIPHERALLY RESTRICTED KAPPA AGONISTS

The pulsatile activity of KNDy neurons is controlled by an interplay of NKB receptors and dynorphin receptors, acting in a reciprocal fashion to generate pulsatile events—intermittently stimulated by NKB and suppressed by dynorphin Kappa agonists bind the dynorphin receptor (AKA kappa opioid receptor, KOR), and inhibit LH pulses, presumably by interfering with kisspeptin and GnRH signaling KOR receptor antagonists stimulate LH pulse frequency Pure kappa agonists cause dysphoria and nausea, peripherally restricted kappa agonists (PRKAs) do not KNDy neurons are located at the interface of the blood brain barrier and may be a target for PRKAs that do not pass the blood brain barrier Hypothesis: PRKAs are effective in treating HF and have minimal side effects

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PERIPHERALLY RESTRICTED KAPPA AGONISTS

Clinical observations suggest postmenopausal women on methadone and some opioids may have ↓ hot flashes and

  • pioid withdrawl ↑ hot flashes (Reed clinical experience)

Kappa agonists bind to the opioid receptor in the hypothalamus and inhibit KNDy neuronal activity

(Navarro, 2009; Wakabayashi, 2010)

Peripherally restricted kappa receptor agonists (PRKA)s do not cross the blood-brain barrier and could theoretically block hot flashes without affecting cognitive brain centers, avoiding opioid side effects (Chen, 2005,

Chavkin, personal communication, 2012)

THE BRAINS

PERIPHERALLY RESTRICTED KAPPA AGONISTS

Double-blind, randomized cross-over study, inpatient research setting, N=12 Moderate-severe hot flashes, ages 48-60 3 interventions in randomized order, on 3 separate days:

  • placebo
  • standard Pentazocine/Naloxone (50/0.5 mg) or
  • low-dose Pentazocine/Naloxone (25/0.25 mg)

IV catheter for luteinizing hormone (LH) blood sampling Skin conductance and Holter monitors placed Subjective hot flash frequency and severity recorded

Oakley AE. Menopause, 2015

LH PULSE AND HOT FLASH OCCURRENCE

Oakley AE. Menopause, 2015

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Kappa Agonist, LH Pulses

p = 0.12*

* Wilcoxon signed rank test

Oakley AE. Menopause, 2015

Kappa Agonist, Hot Flash Frequency

p < 0.05*

* Wilcoxon signed rank test

Oakley AE. Menopause, 2015

SUMMARY KNDY NEURON MANIPULATION

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HF freq HF sev QOL sleep Sexual function Side effects MLE 4901 40 mg bid (Prague J) ↓ ↓ ↑ HFRDIS N=8 BL 1.1(0.6) vs 6.4(0.8) p=0.008 ↑ LEEDS No change (sexual function domain, MENQOL) ↑ LFTs ESN364 90mg bid (Fraser G) ↓ ↓ ↑ HFRDIS Greene Sheehan ↑ LEEDS No change (sexual function domain, Greene)

No diff from plcbo overall, GI 14% vs 0% plcbo

NT-814 (Anderson R; Pawsey S) ↓ ↓ ? ↓ interrupt- ion ?

Mild somnolence higher dose

KA (Oakley A) ↓

  • ?

? ?

Dysphoria, nausea

SUMMARY KNDY INTERVENTIONS

Rapid effect within 3 days, full effect within 7-14 days Observed efficacy appears greater than any other proven non-hormonal product (SSRI, SNRI, or gabapentin) Single oral daily dose desired Side effect profiles promising, but are currently limiting further development of some products (e.g. Millendo, MLE 4901, Pavinetant) Long term studies will determine whether this class of drugs will become part of our RX armamentarium

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REMAINING QUESTIONS

If overall LH is decreased by KNDy RX , what effect will this have on postmenopausal androgens and sexual function? NK3 receptors are present throughout the brain and the body (e.g. liver). How to target just KNDy neurons and the adjacent thermoregulatory center with these novel therapeutics? Will drug development be handicapped by the ubiquitous nature of NK receptors or will this be a bonus in the end (e.g. improved metabolic profile, sleep)? PRKAs theoretically hold promise, but will they hold up to the test of time (rigorous RCTs)?