new drugs: what’s in the pipeline? john b. buse, md, phd ... · new drugs: what’s in the...

New Drugs: What’s in the Pipeline?

John B. Buse, MD, PhD Saturday, February 18, 2017

11:30 a.m. – 12:15 p.m. There is an enormous pipeline of drugs and products for the management of diabetes and related comorbidities. . Some recent reports provide listings of 221 companies with development programs in type 2 diabetes alone. Near term there are no new classes of antihyperglycemic medications on the horizon though a variety of novel and theoretically advantageous application of currently available classes of medications. About ½ my presentation with focus on those drugs that are likely to be available in the next 24 months and about ½ my presentation on new classes of drugs where the potential to address unmet needs seems reasonable. References: 1. Medicine in Development: Diabetes.

http://phrmadocs.phrma.org/files/dmfile/diabetes20144.pdf. Accessed jan 27, 2017 2. The 2017 Pipeline Report: What to know about Next Year’s Launches.

http://www.mmm-online.com/pipeline/the-2017-pipeline-report-what-to-know-about next-years-launches/article/574743/4/?publishdate=False&timestamp=636159234303160779. Accessed Jan 27, 2017

3. Martinussen C, Bojsen-Moller KN, Svane MS, Dejgaard TF, Madsbad S. Emerging drugs for the treatment of obesity. Expert Opin Emerg Drugs. 2016 Dec 16:1-13. [Epub ahead of print] PubMed PMID: 27927032.

4. Hedrington MS, Davis SN. Discontinued drug therapies to treat diabetes in 2015. Expert Opin Investig Drugs. 2017 Feb;26(2):219-225. doi:10.1080/13543784.2017.1274732. PubMed PMID: 27997806.

http://www.mmm-online.com/pipeline/the-2017-pipeline-report-what-to-know-about

New Drugs: What’s in the Pipeline?

John B. Buse, MD, PhDVerne S. Caviness Distinguished Professor

Chief, Division of EndocrinologyDirector, NC Translational and Clinical Sciences Institute

Executive Associate Dean, Clinical ResearchUniversity of North Carolina School of Medicine

Thanks to Jay Skyler

Duality of Interest DeclarationI report the following potential duality/dualities of interest:

Board Member/Advisory Panel: None

Speaker’s Bureau: NoneConsultant: PhaseBio, Insulin AlgorithmsStock/Shareholder: PhaseBio, Insulin AlgorithmsResearch Support: AstraZeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, J&J, Lexicon, Novo Nordisk, Sanofi, TheracosOther (advisor under contract between UNC and the company): Adocia, AstraZeneca, Dance Biopharm, Dexcom, Elcylex, Eli Lilly, Fractyl, GI Dynamics, Shenzen HighTide, Intarcia, Lexicon, Merck, Metavention, Novo Nordisk, Orexigen, Quest, vTv TherapeuticsTravel Support: in conjunction with above-mentioned activities

Type 2 Diabetes Companies

Addex Therapeutics LtdAdociaAdvinus Therapeutics Ltd.Aegis Therapeutics, LLCAFFiRiS AGAlchemia LimitedAlize Pharma SASAlphaMabCo., LtdAmarantus Bioscience HoldingsAmbrx, Inc.Amgen Inc.Anchor Therapeutics, Inc.AntriaBio, Inc.Aphios CorporationAraim Pharmaceuticals, Inc.Arisaph Pharmaceuticals, Inc.ArisGen SAArray BioPharma Inc.Artery Therapeutics, Inc.Astellas Pharma Inc.AstraZeneca PlcAUS Bio LimitedAvaxia Biologics, Inc.Bayer AGBeta‐Cell NVBetagenon ABBiocon LimitedBiodel Inc.Biogenomics LimitedBioLingus AGBioRestorative Therapies, Inc.BioTherapeutics Inc.BioTime, Inc.Biscayne Pharmaceuticals, Inc.Boehringer Ingelheim GmbHBoston Therapeutics, Inc.Braasch Biotech LLCBristol‐Myers Squibb CompanyC4X Discovery Holdings PLCCadila Pharmaceuticals LimitedCaldan Therapeutics Limited

Type 2 Diabetes ‐ Pipeline Review, H1 2016. ID: 3734789. April 2016. 1329 pages. Global Markets Direct. Available at http://www.researchandmarkets.com/research/3qn64l/type_2_diabetes. $2500

Cardax Pharmaceuticals, Inc.Carlina Technologies SASCarmot Therapeutics, Inc.Catabasis Pharmaceuticals, Inc.Celon Pharma Sp. z o.o.Chipscreen Biosciences LtdChong Kun Dang Pharm. Co.CJ HealthCare Corp.CohBar, Inc.Connexios Life Sciences Pvt.Corium International, Inc.CSL LimitedCureDM, Inc.CymaBay Therapeutics, Inc.Daewoong Pharmaceutical Co.Daiichi Sankyo CompanyDance Biopharm Inc.Debiopharm International SADelpor, Inc.Diabetica LimitedDiabetology (Products) LtdDiaMedica Inc.Diasome Pharmaceuticals, Inc.DiscoveryBiomed, Inc.Eisai Co., Ltd.Elcelyx Therapeutics, Inc.Eli Lilly and CompanyenGene, IncEnzo Biochem, Inc.Epichem Pty LtdEsperion Therapeutics, Inc.Eternygen GmbHEuroscreen S.A.Evotec AG

F. Hoffmann‐La Roche Ltd.FibroStatin SLFlamel Technologies S.A.Foresee Pharmaceuticals, LLCGenerex BiotechnologyGenfit SAGenovate Biotechnology Co.Gero CorpGeropharmGlaxoSmithKline PlcGlide PharmaceuticalGlucox Biotech ABGW Pharmaceuticals PlcHadasitMedical ResearchHalozyme Therapeutics, Inc.HanAll Biopharma Co., Ltd.Handok Inc.Hanmi Pharmaceuticals, Co.Heptares Therapeutics LimitedHua Medicine Ltd.Hyundai Pharmaceutical Co.Immuron LimitedInnopharmax Inc.Intarcia Therapeutics, Inc.Integral Molecular, Inc.IntelliCell BioSciences Inc.Intercept Pharmaceuticals, Inc.Intrexon CorporationIonis Pharmaceuticals, Inc.IPCA Laboratories LimitedIslet Sciences, Inc.iTherX, Inc.Japan Tobacco Inc.Jeil Pharmaceutical Co., Ltd.

Jenrin Discovery, Inc.JHL Biotech, Inc.Jiangsu Hengrui Medicine Co.Johnson & JohnsonKadimastem Ltd.Kadmon Corporation, LLCKareus Therapeutics, SAKissei Pharmaceutical Co., Ltd.Lexicon Pharmaceuticals, Inc.LG Life Science LTD.Ligand Pharmaceuticals, Inc.Lonestar Heart, Inc.Longevity Biotech, IncMagnus Life ScienceMedesis Pharma S.A.Medestea Res. & Prod. S.p.A.MedImmune, LLCMellitech SASMerck & Co., Inc.Mesoblast LimitedMetabolic Solutions Dev. CoMetabolys SASMI.TO. Technology S.r.L.MicroBiome Therapeutics LLCMidaSol Therapeutics LPMitsubishi Tanabe PharmaNaia LimitedNeurimmune Holding AGNeurocrine Biosciences, Inc.NGM Biopharmaceuticals, Inc.Nimbus Therapeutics, LLCNOD Pharmaceuticals, Inc.Nordic Bioscience A/SNovartis AG

NovaTarg Therapeutics, IncNovo Nordisk A/SNoxxon Pharma AGOmeros CorporationOPKO Health, Inc.Oramed Pharmaceuticals, Inc.Orbis Biosciences, Inc.Panacea Biotec LimitedParas BiopharmaceuticalsPeptron, Inc.Pfizer Inc.PharmaIN CorporationPhaseBio Pharmaceuticals, Inc.Pivot Pharmaceuticals IncPoxel SAProgen PharmaceuticalsPrometheon Pharma, LLCProMetic Life Sciences Inc.Prothena Corporation PlcPurzer Pharmaceutical Co., Ltd.Reata Pharmaceuticals, Inc.Red Glead Discovery ABRegenMedTX, LLCreMYND NVRhizen Pharmaceuticals S.A.Rhythm Pharmaceuticals, Inc.Saniona ABSanofiSanwa Kagaku Kenkyusho Co.SATT Conectus Alsace SASSBI Pharmaceuticals Co., Ltd.Seres Therapeutics, Inc.Serodus ASASerometrix, LLCSevion Therapeutics, Inc.Shanghai FosunShanghai Pharmaceutical Co.

Shantani Proteome AnalyticsShionogi & Co., Ltd.Sihuan Pharmaceutical Holdings Group Ltd.Sirona Biochem CorpSJT Molecular Research, S.L.SK Chemicals Co., Ltd.Sprint Bioscience ABStarpharmaHoldings LimitedStelic Institute & Co., Inc.Strongbridge Biopharma plcSumitomo Dainippon PharmaTaisho PharmaceuticalTakeda PharmaceuticalTeijin Pharma LimitedTheracos, Inc.Therapix Biosciences LtdThermalin Diabetes, LLCThetis Pharmaceuticals LLCToray Industries, Inc.Torrent PharmaceuticalsTransgene Biotek LimitedTWi Pharmaceuticals, Inc.Uni‐Bio Science Group Ltd.Valeant PharmaceuticalsVicore Pharma ABViking Therapeutics, Inc.Virobay Inc.Vivus, Inc.vTv Therapeutics LLCVybion, Inc.XBiotech USA, Inc.Xenetic Biosciences (UK)Xizang Haisco Pharmaceutical Group Co., Ltd.XL‐protein GmbHXOMA CorporationYuhan CorporationYungjin Pharm. Co., Ltd.Zafgen Inc.Zealand Pharma A/SZensun (Shanghai) Sci & TechZydus Cadila Healthcare

P&T “Pipeline Plus”

Fellner C. P&T. 41(10):650‐653. Investigational. Not FDA approved.

Ertugliflozin

Investigational. Not FDA approved.


• Rapid

– Technosphere (inhaled)

– Lispro U‐200

– Human U‐500 pen (not so rapid)

• Long

– Degludec (U‐100, U‐200)

– Glargine (biosimilar U‐100, U‐300)

• Patch pumps

• GLP‐1RA plus basal insulin

• Future

– Ultra‐rapid (FiAsp, Biochaperone insulin, LY900014)

– Smart insulin

New insulins

Combination Therapy:GLP‐1RA + Insulin

IGlarLixi Pen Injection

3:1 ratio of insulin glargine to lixisenatide

provides a glargine dose range of 30 to 60 units

and a lixisenatide dose range of 10 to 20 ug.

mITT by MMRM (mixed‐effect model with repeated measures)

p<0.0001 for all comparisons

7.3%

6.8%

6.5%

S BL 8 12 24 30 30LOCF

iGlar

Lixi

iGlarLixi vs iGlar and vs Lixi in T2DM on Metformin: LixiLan‐O

Trial

Rosenstock J et al. Diabetes Care 2016; 39:2026‐2035

BL 4 8 12 24 30 30LOCF

18

iGlarLixi

74

5659

40

33

19

0

10

20

30

40

50

60

70

80

Percentage of Patients (%)

HbA1c <7% HbA1c ≤6.5%

iGlarLixiiGlarLixi

*Weighted average of proportion difference between treatment groups

p<0.0001

p<0.0001

p<0.0001

p<0.0001

A1c Targets at 30 weeks

Rosenstock J et al. Diabetes Care 2016; 39:2026‐2035

mITT

BL, baseline; CI, confidence interval; LS, Least squares; LOCF, Last observation carried forward mITT, modified intent‐to‐treat; MMRM, mixed‐effect model with repeated measures; S, Screening; SE, standard error

6.0

6.5

7.0

7.5

8.0

8.5

9.0

6.0

6.5

7.0

7.5

8.0

8.5

9.0

7.5

–0.62

iGlar

8.5

8.1

LixiLan‐L: Mean HbA1c ChangeHbA1c over time (%)

iGlarLixi

iGlar

6.9%

7.5%

S BL 8 12 24 30 30LOCF

LS mean difference 95% CI, p‐value

–0.52 (–0.633 to –0.397)p<0.0001

iGlarLixi

8.5

8.1

Screening

Baseline

6.9

–1.13

Week 30

LS mean change

Mean ±SE

Week

Aroda V, et al. Diabetes Care 2016; 39:1972‐1980

IDegLira – Pen Injection

DUAL I: A1c Efficacy

15

8.5

8.0

7.0

6.5

7.5

6.0

HbA1c (%

)

0.0

0 4 6 32 4412 15 20 24 28 36 40 48 52

Weeks

‐1.21% 7.1%

‐1.40% 6.9%

‐1.84%* 6.4%

= ‐0.65[‐0.76; ‐0.53]

= ‐0.46[‐0.57; ‐0.34]

95%CI

95%CI

HbA1c EOT

Liraglutide (N=414)IDegLira (N=83) Degludec (N=413)

Week 26 Week 52

Gough et al. Lancet Diabetes Endocrinol 2014; 2:885‐893. Gough et al. Diabetes Obes Metab 2015; 17:965‐973

Proportion of Subjects Achieving A1c Targets


Body Weight

17

92

90

86

84

88

Weight (kg)

5 10 3515 20 25 30 40 45 50 55Study week

IDeg IDegLira Lira

Study 3697

First 26 weeks Extension


DUAL 2: Study design

Patients with type 2 diabetes(N=398)

0 26 weeksRandomised 1:1

Double-blind

IDeg + metformin(n=199)

IDegLira + metformin(n=199)

Inclusion criteria

• Type 2 diabetes

• HbA1c 7.5–10.0%

• BMI ≥27 kg/m2

• Age ≥18 years

• basal insulin (20-40U) + metformin +/- SU or glinidesU

Titrate to targetSMBG

(4–5 mmol/L)[72-90 mg/dL]

Maximum dose(50 dose steps /

50 units)

N: number of randomised subjects, excluding subjects from Site 105 (8 subjects for IDegLira and 7 subjects for IDeg); SMBG, self-monitoring blood glucose; SMBG measured using a glucometer which was calibrated to convert blood glucose measurements to plasma glucose valuesNN9068-3912; IDegLira vs IDeg in T2DM Buse JB, et al. Diabetes Care. 2014; 37:2926-33.

DUAL 2: Daily dose of IDeg component

10

14

18

22

26

30

34

38

42

46

50

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Mean values with error bars (standard error mean) based on safety population and LOCF imputed dataEstimated treatment differences are from an ANCOVA analysis

Time (weeks)

Dai

ly d

ose

(U)

End of trial dose:IDegLira: 45U

IDeg: 45UTreatment difference:

-0.02 U p=ns

~65% at max dose of IDegLira, of which ~60% were at target (<7.0%)

IDegLira (n=199)

IDeg (n=199)

NN9068-3912; IDegLira vs IDeg in T2DM Buse JB, et al. Diabetes Care. 2014; 37:2926-33.

DUAL 2: Change in body weight over time

Mean values with error bars (standard error mean) based on FAS and LOCF imputed dataEstimated treatment differences are from an ANCOVA analysis

-7.7-6.9-6.1-5.3-4.5-3.7-2.9-2.1-1.3-0.50.31.1

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Cha

nge

in b

ody

wei

ght

(kg)

Treatment difference: −2.51 kg (5.52 lb)

p<0.0001

Time (weeks)

IDegLira (n=199)

IDeg (n=199)

NN9068-3912; IDegLira vs IDeg in T2DM

Cha

nge

in b

ody

wei

ght

(lb)

Buse JB, et al. Diabetes Care. 2014; 37:2926-33.

DUAL 2: Confirmed hypoglycaemia

Mean values based on SASEstimated treatment ratios are from a negative binomial model

Time (weeks)

0.00.10.20.30.40.50.60.70.80.91.01.11.21.31.4

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Rate ratio: 0.66p=0.13

Cum

ulat

ive

epis

odes

per

sub

ject

IDegLira IDeg

HbA1c (%) 6.9 8.0

IDegLira (n=199)

IDeg (n=199)


DUAL 2: Percentage of subjects with nausea

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (weeks)

Sub

ject

s (%

)

Data are from SAS

0

IDegLira (n=199)

IDeg (n=199)


Combination Therapy:GLP‐1RA + SGLT2 Inhibitor

GLP1‐RA + SGLT2 Inhibitor Exenatide‐QW and Dapagliflozin

Frias et al. Lancet Diabetes Endocrinology 2016; 4:1004‐1016

GLP1‐RA + SGLT2 Inhibitor Exenatide‐QW and Dapagliflozin

Frias et al. Lancet Diabetes Endocrinology 2016; 4:1004‐1016

Implanted GLP1 RA Preparation

Intarcia Delivery Technology

Mini‐Pump Size of a matchstick!

Continuous Subcutaneous Delivery of Exenatide

Continuous Subcutaneous Exenatide with ITCA 650*

Time (days)

Release Rate

(mcg per day)

SemipermeableMembrane

PistonOsmoticEngine

Drug Reservoir withNovel Stabilizing Suspension

DiffusionModerator Immediate Release

Exenatide

Sub‐dermal placement once/twice yearly

Done in a brief, in‐office, sterile procedure by MD or NP/PAs

Approved reimbursement codes for similar procedures

Osmotic Mini‐Pump

Continuous zero order delivery for up to a full 12 months

Novel formulation stabilizes peptides at body temps for years

* In development Intarcia Website – Accessed Jan 18 2016Investigational. Not FDA approved.



Intarcia Website – Accessed Jan 18 2016*In development Investigational. Not FDA approved.



* In development Intarcia Website – Accessed Jan 18 2016Investigational. Not FDA approved.

Oral GLP1 Preparations

Marso SP, et al. N Engl J Med. 2016; 375: 1834‐1844.


Oral Semaglutide* Dose Dependent Change in A1c

Novo Nordisk A/S Website – Accessed Jan 18 2016*Investigational. Not FDA approved.

Oral Semaglutide* Dose Dependent Change in Body Weight

Novo Nordisk A/S Website – Accessed Jan 18 2016*Investigational. Not FDA approved.

IN THE DISTANT FUTURE

Oral TTP273 – Non-Peptide GLP1-RA Dose Dependent Change in Glucose

Phase 1 Trial

Vtvtherapeutics.com– Accessed Jan 18 2016Investigational. Not FDA approved.

Glucokinase: The Physiological Glucose‐sensor

February 2017 vTv Therapeutics LLC 36

In humans, abnormal GK activity due to activating or inactivating mutations is linked to hyperglycemic and hypoglycemic conditions respectively

In humans, loss of function mutations on the GKRP are associated with increased plasma lipids (Rees et al. J Clin Invest. (2012) 122, 205‐217)

In rodents, GKRP KO mice showed:• Decrease of GK expression in the liver• Glucose intolerance• Insulin resistance

TTP399: Tissue Selectivity and Preservation of Physiological Regulation to Avoid Pitfalls


new drugs: what’s in the pipeline? john b. buse, md, phd ... · new drugs: what’s in the...

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