Wave Life Sciences : Speaker Presentation

Analyzing Real-World Evidence

Regarding Efficacy, Adherence and

Usage of GLP-1 Drugs and New

Therapeutic Directions

Ginnie (Hsiu-Chiung) Yang, PhD

SVP Translational Medicine, Wave Life Sciences

2nd annual Obesity and Weight Loss Drug Development Summit

June 11-13, 2024, Boston, MA

		BMI is associated with increased
Obesity is not just		mortality in individuals who are
64	overweight or obese

"too much weight"

• Defined as 'abnormal or excessive fat accumulation that presents a risk to health'.2
• More than 200 complications are linked to obesity -- explains increased, related morbidity and mortality and 4 million related deaths worldwide in 2015.3,4
• QoL of people with obesity or overweight is often impaired and lifespan significantly reduced.5
• High BMI is associated with decreased life expectancy of up to 10 years
• For every 5 kg/m2 BMI increment above the range of 22.5-25.0 kg/m2, overall mortality is increased by 30%.6

Yearly deaths per 1000 (95% CI)

32

16

8

Male

Female

15	20	25	30	35	40	50

Baseline BMI (kg/m2)

2

1. touchREVIEWS in Endocrinology. 2022; 18(1):35-42 ; 2. World Health Organization. Obesity and overweight. 2021. www.who.int/news-room/fact-sheets/detail/obesity-and-overweight; 3. Yuen MS, Lui DT, Kaplan LM, et al. Obesity Week 2016, New Orleans, LA, 31Oct-4 Nov. Poster T-P-3166; 4. Afshin A, Forouzanfar MH, Reitsma MB, et al. N Engl J Med. 2017;377:13-27; 5. Lancet. 2016;388:776-86; 6. Lancet. 2009;373:1083-96

Future weight loss medications aim to

improve efficacy, tolerability, and adherence

Real world evidence for approved GLP-1RA drugs provide key directions for further improvements

3

touchREVIEWS in Endocrinology. 2022; 18(1):35-42

Real-World Evidence on the impact of the GLP-1 class on patient experience

• Positive experience - impressive weight loss
• Negative experience - adverse events

4

Real-World Weight Loss Outcomes for Individuals who are Overweight or Obese Treated with Semaglutide

Patients with T2D experience smaller magnitude of weight loss than those without T2D

Error bars = SD

eHR Mayo Clinic Health System 01/01/2021 to 03/15/2022

Categorical Percentage Weight Loss at 3 and 6 Months (semaglutide)

eHR Mayo Clinic Health System 01/01/2021 to 03/15/2022

Semaglutide delivers similar weight-loss for patients without bariatric surgery, as well as in those with inadequate body weight reduction after bariatric surgery

				28
80%
	84		(71.8)
				56
70%		(65.1)
				(62.2)
60%
50%
									14
								42
									28
40%						(35.9)
							(32.6)
					(31.1)
30%

20%	10	3	7
10%	(7.8)	(7.7)	(7.8)

0%

>5%		>10%	>15%

Percentage weight loss

BS, bariatric surgery; BS+, patients with a history of BS; BS, patients without a history of BS

5

JAMA Netw Open. 2022;5(9):e2231982; Obesity 2023; 32(1): 50-58

Negative experience associated with GLP-1RA treatment - Adverse events (AE)

Mechanism-related AE -

NON-CNS

• Hypoglycaemia1
• Gastrointestinal1 - abdominal pain, nausea, vomiting, diarrhea, belching, heartburn, and GI bleeding
• Pancreatitis, gallbladder disease or biliary diseases1,2
• Pulmonary aspiration- intestinal blockage, paralytic ileus3

Mechanism-related AE -	Induced by Rapid weight
CNS		loss
• Psychiatric adverse events	•	Hair loss - Telogen
-	depression4		Effluvium6,7
-	suicidal thoughts and	•	Cosmetic - Ozempic butt or
	actions4,5		face8

• self-injuriousideations5
• Suppression of general reward system5

• Neoplasms - pancreatic cancer, and/or thyroid cancer/carcinoma, and medullary thyroid cancer1
• Loss of muscle9,10,11

6

1. Front Endocrinol (Lausanne) (2021)12:645563; 2. Front Endocrinol (Lausanne) (2023) 14:1214334; 3. Anaesth Rep (2024) 12(1):e12278; 4. Front. Psychiatry 14:1238353; 5. EuropeanNeuropsychopharmacology82(2024)82-91; 6. Cureus (2021) 13(4):e14617; 7. Medicina (Kaunas) (2024) 60(2):325; 8. Plast Reconstr Surg Glob Open. (2024) 12(1): e5516; 9. Eur Rev Med Pharmacol Sci (2023) 27(20):9908-9915; 10. Curr Diabetes Rev (2021) 17(3):293-303; 11.Osteoporos Int (2018) 29(12):2639-2644

Non-CNS Mechanism related Adverse Events for GLP-1RA

Incidence of gastrointestinal adverse events due to treatment with GLP-1RA

GI related AE

Risk of pancreatic cancer

Semaglutide

Dulaglutide

Liraglutide

Exenatide

Abdominal pain

Constipation

Diarrhea

Nausea/Vomiting

GI bleeding

Gastroparesis

Pancreatitis

ALL of Us Research Program Database Version 7, 10,328 new GLP-1RA users. 36.2% were on semaglutide (n = 3739), 29.8% were on dulaglutide (n = 3079), 29.3% were on liraglutide (n = 3031), and 4.6% were on exenatide (n = 479)

FAERS adverse event (AE) reports (between 1 January 2004 and 31 December 2020) were used to investigate the correlation between GLP-1RAs and pancreatic carcinoma. A total of 3073 pancreatic carcinoma cases were related to GLP-1RAs. ROR reporting odds ratio, CI confidence interval, PRR proportional reporting ratio, IC information component, IC025 the lower limit of a 95% credibility interval for the IC, - not available, EBGM empirical Bayesian geometric mean, EBGM05 the lower limit of a 90% one-sided CI of EBGM

7

Pharmaceuticals (Basel). 2024 Feb; 17(2): 199; International Journal of Clinical Pharmacy (2023) 45:689-697

Real-World Evidence for GLP-1RA-related psychiatric adverse events demonstrates fast onset and reversibility

Psychiatric AEs have fast onset, do not appear to increase with improved efficacy, and are rare

GLP-1RA)-related psychiatric adverse events (AEs) based on the FAERS database (2004-2023)1

Age and sex distribution for psychiatric adverse events, semaglutide, liraglutide and tirzepatide2

Fast onset for GLP-1RA-related psychiatric adverse events3

Red - women, blue - men, Black - unspecified

8

1. Front. Endocrinol.(2024) 15:1330936; 2. International Journal of Clinical Pharmacy (2024) 46:488-495; 3. Front. Endocrinol.(2024) 15:1330936

Semaglutide-induced weight loss is associated with reduction in muscle mass

Body-weight loss represents combination of a larger loss of fat mass and a smaller loss of muscle mass

Treatment with semaglutide led to significant loss of fat and skeletal muscles (RWE)1

Higher degree of lean mass loss is associated with greater body weight reduction (STEP1)2

Reduction of total lean mass is greater with semaglutide treatment compared to SGLT2i (SUSTAIN8)3

***p< 0.001

From November 2021 to November 2022, a total of 53 patients with obesity (BMI ≥ 28 kg/m2) who received 24 weeks of treatment with semaglutide at the Second Affiliated Hospital of Guangxi Medical University

Loss of muscle mass due to reduced nutritional status is a general physiological response

9

1. European Review for Medical and Pharmacological Sciences (2023) 27: 9908-9915; 2. N Engl J Med 2021;384:989. 3. Diabetologia (2020) 63:473-485

Medications inducing reduction in the intake of nutrients also bring on reduction in skeletal muscles mass

Medication-induced reduction in nutrition appears to activate general physiological response

00

-2

-4

-6

-8

-10

Total weight loss (%)		Reduction of body fat (Kg)		Reduction of visceral fat (cm2)			Loss of skeletal muscle (Kg)
						0
	0
						-0.5
	-2		0

-6

-20

-2.0

-8

-30-8

-2.5

0M

0M

2M

4M

6M

2M

4M

6M

2M

6M

0M

4M

2M

4M

6M

0M

Visit

Visit

Visit

Visit

Anti-Obesity drugs

205 adults aged 19-65 years who had obesity or overweight with obesity-related comorbidities, who were

Orlistat

prescribed AOMs by two family medicine specialists at the obesity clinics of Kyungpook National University

Lorcaserin

Hospital and Kyungpook National University Chilgok Hospital between March 2015 and December 2020.

Naltrexone/Bupropion

Orlistat (12), Lorcaserin (24), Naltrexone/Bupropion (17), Liraglutide (62), Phentermine/Topiramate (51),

Liraglutide

Phentermine/Topiramate

Phentermine (39)

Phentermine

10

Drug Design, Development and Therapy 2024:18