Treatment With Oral Octreotide Capsules May Not Adversely Affect Glycemic Control in Patients With Acromegaly: Results From the Phase 3 CHIASMA OPTIMAL Study

Samson SL, Nachtigall LB, Fleseriu M, Labadzhyan A, Waligorska A, Molitch M, Ludlam WH, Patou G, Haviv A, Biermasz N, Strasburger CJ, Kennedy L, Melmed S

Disclosures

• Dr. Samson is a consultant for Chiasma; is an advisory board member for Novartis and Chiasma; has received grants from Novartis; and is a research investigator for Chiasma, Corcept, Novartis, and OPKO.

Octreotide Specificity for SSTs May Offer Balanced Glycemic Control

1. Chaudhry R, et al. MJAFI. 1997;53:293-294; 2. Octreotide LAR [prescribing information]; 3. Schmid H, et al. Endocrine. 2016;53:210-219; 4. Henry RR, et al. J Clin Endocrinol Metab. August 2013; 98(8):3446–3453.

Safety, including measures of glucose homeostasis, of oral octreotide capsules was evaluated in CHIASMA OPTIMAL, a

prospective phase 3 study in patients whose acromegaly was controlled by injectable SRL treatment

• In trials involving patients previously on somatostatin receptor ligands (SRLs), hyperglycemia occurred in 15% receiving long-acting octreotide2

• Glucagon-producing α cells mostly express SST2, whereas SST5 and SST2 are found in insulin-producing β cells3

• The ratio of affinity to SSTs mediates the balance of glucose production and thus potential hyperglycemia risk4

OOC, oral octreotide capsule; SRL, somatostatin receptor ligand; SST, somatostatin receptor.

Octreotide binds with a high affinity for both SST5 and SST21

Octreotide

Overall Glucose Homeostasis

Glucagon

Insulin

β cells

α cellsSST2

SST5 SST2

The Mechanism of Oral Octreotide Capsules

• MYCAPSSA®is an investigational oral octreotide formulation designed for intestinal absorption using an excipient mixture (TPE®), in an enteric-coated hard gelatin capsule1,2

• TPE induces local, transient, and reversible paracellular permeation, enabling orally administered octreotide to be absorbed into systemic circulation1,2

• This formulation is designed to prevent early gastric release

.

Peptide

TPE

Small intestine

Lumen

Epithelium

Blood

Octreotide

Unmodified octreotide peptide and TPE® (medium chain fatty

acid C8, inert excipients) in enteric-coated capsule

TPE® transiently and reversibly openstight junctions in the intestinal barrier

Figure adapted from Melmed S. Nat Rev Endocrinol. 2016;12(2):90-98.

Mechanism of Oral Octreotide Capsules1-3

1. Karsdal MA, et al. Br J Clin Pharmacol. 2015;79(5):720-732. 2. Tuvia S, et al. J Clin Endocrinol Metab. 2012;97(7):2362-2369. 3. Melmed S. Nat Rev Endocrinol. 2016;12(2):90-98.*conditional trade name. TPE, transient permeability enhancer.

CHIASMA OPTIMAL: Inclusion/Exclusion Criteria

Key Inclusion criteria

• Adults aged ≥18 years at first screening• Evidence of active disease (IGF-I ≥1.3 ×

ULN following the most recent pituitary surgery)

• Received injectable SRL therapy for ≥6 months

• On a stable dose of injectable SRL therapy for ≥3 months

• Average IGF-I ≤1.0 x ULN of 2 screening assessments

Key Exclusion criteria

• Receiving off-label doses of injectable SRLs

• Undergone radiotherapy any time in the past or pituitary surgery within 6 months prior to screening

IGF-I, insulin growth factor-1; ULN, upper limit of normal.

CHIASMA OPTIMAL: Study Design

aEarly study medication discontinuations (both arms), to be followed ≤36 wks, per protocol. bPer study protocol, discontinuations were considered nonresponders regardless of clinical response at the time of discontinuation (nonresponse imputation). Exploratory analyses were performed utilizing the last observation carried forward analysis, as well as a completer analysis of response among the subgroup that completed the entire 36 weeks on study drug. DPC, double-blind placebo-controlled; OLE, open-label extension.

OLEDPC (36 weeks)

Baseline

Placebo

N=28

N=28

36 weeks 34

Last SRL injectionScreening

Withdrawal

Primary endpoint

IGF-I

OOC

Rescue injection

OOC 60mg

Pre-defined withdrawal criteria (both arms)a,b

• IGF-I ≥1.3 x ULN for 2 consecutive visits on the highest dose and exacerbation of clinical signs/symptoms

• Early terminated patients followed ≤36 weeks on injections, per protocol

Screening• The last SRL injection can be within the

screening period as long as baseline is the end of the injection interval

• Screening Visit 2 is within 2 weeks from baseline/randomization

40 mg 60 mg80 mg

40 mg80 mg

CHIASMA OPTIMAL: Efficacy Endpoints

aMean calculated from average of 2 assessments within 2 weeks prior to randomization.

Mean IGF-I for the OOC cohort was

maintained within the normal range

Mean IGF-I at Baseline and end of DPC perioda

0.80 0.840.97

1.69

0

0.5

1

1.5

2

2.5

Oral Octreotide Placebo

Mea

n IG

F-1

(x U

LN)

Treatment group

Baseline End of treatment

CHIASMA OPTIMAL: Efficacy Endpoints

OOC(N=28)

Placebo(N=28) P-Value

Primary endpoint

Proportion maintaining IGF-I response, % 58 19a 0.008

Secondary endpoints

Proportion maintaining GH response, % 78 30 0.001

Median time to IGF-I >1.0 x ULN, wk Not met 16 <0.001

Median time to IGF-I >1.3 x ULN, wk Not met 16 <0.001

Rescued to prior injectable, % 25 68 0.003

aAll 19% of the placebo responders (n=5) continued in the OLE based on PI discretion, because they either had lost response at some point in the study, or had continuing acromegaly symptoms.

CHIASMA OPTIMAL: Safety ResultsOOC Placebo

Subjects with: n % n %

≥1 TEAE 28 100.0 27 96.4≥1 Treatment-related TEAE 18 64.3 15 53.6

≥1 SAE 2 7.1 1 3.6

≥1 Treatment-related SAEs 0 0.0 0 0.0≥1 Maximum severity severe TEAE 3 10.7 7 25.0

≥1 TEAE leading to study drug discontinuation 2a 7.1 1 3.6

≥1 TEAE of special interest (acromegaly symptoms)b 15 53.6 26 92.9

• Most TEAEs were mild or moderate

• GI AEs were transient

• No deaths were reported during the DPC period

• Overall, OOCs were well tolerated; no new/unexpected safety signals were observed

• Three patients in the OOC group experienced severe TEAEs:

￮ Gastrointestinal (abdominal discomfort, dyspepsia, nausea, vomiting)

￮ Nervous system disorders (headache)

aTEAEs leading to study drug discontinuation in two patients the OOC group were nausea, vomiting, abdominal discomfort, heartburn and headache. bTEAEs of special interest includes: headache, fatigue, perspiration, soft tissue swelling, arthralgia, dysglycemia, hypertension, or other signs in view of investigator as related to acromegaly.SAE, serious adverse event; TEAE, treatment-emergent adverse event.

AEs Related To Blood Glucose Control

Minimal shifts in glucose control were consistent with class effect for first-generation SRLs

AE, adverse event; OOC, oral ocreotide capsules; SRLs, somatostatin receptor ligandsNOTE: Blood glucose increased and hyperglycemia were calculated by the recording of AEs by clinicians according to MedDRA terms.a1 of these AEs was deemed related to study drug by the investigator. bDeemed possibly related to study drug.

OOC (n=28)

MedDRA Listing n %

Hypoglycemia 1 3.6

Blood glucose increaseda 3 10.7

Hyperglycemiab 1 3.6

Glucose Control Throughout the DPC Period

In the OOC group (n=28)

• 19 patients had normal glucose levels at baseline and EOT (67.9%)

• 3 patients stayed within the same elevated range at EOT as they were at baseline(10.7%)

• 1 patient was in a lower range by EOT(3.6%)

• Shifted from mild elevation to normal range

• 5 patients were in a higher range by EOT(17.9%)

• All shifted from normal range to a mild elevation

• 4 remained on OOC throughout the DPC, 1 discontinued due to treatment failure

EOT, end of treatment.

Normal Range BL-EOT

LowerHigher

Same

0

1

2

3

4

5

6

7

8

9

10

11

Baseline EOTSe

rum

glu

cose

(mm

ol/L

)

Serum glucose levels from baseline to EOT(OOC group, n=28)

LLN-ULN

Mild Elevation

Elevated

0

18

36

54

72

90

108

126

144

180

198

162 Serum glucose (m

g/dl)

Elevated: >8.9 – 13.9 mmol/L (>160.2-250.2 mg/dl)Mild Elevation: >6.9 – 8.9 mmol/L (>125-160.2 mg/dl)LLN-ULN: 3.3 – 6.9 mmol/L (59.4-125 mg/dl)

Serum Glucose From Baseline to End of Treatment Was Consistent

• Glycemic control from baseline to EOT shifted from normal to high HbA1c in 1 patient in OOC group

Mean serum glucose and

HbA1c remained consistent from

baseline to EOT in the study

Glucose levels in OOC group during the DPC period

Seru

m G

luco

se (m

moI

/L)

Visit Week

2.6

3.6

4.6

5.6

6.6

7.6

8.6

9.6

10.6

11.6

12.6

Baseline 4 8 12 16 20 24 28 32 34 36

HbA1c, hemoglobin A1c.

Baseline Last measurement while receiving

OOCa

aMeasurement at:• Week 36 for patients completing DPC on OOC• Last measurement before rescue therapy in patients discontinuing OOC

226.8

208.8

190.8

172.8

154.8

136.8

118.8

100.8

82.8

64.8

46.8

Serum G

lucose (mg/dL)

Conclusions

• OOCs showed maintenance of glycemic control and an excellent safety profile for patients previously treated with injectable SRLs

• Minimal shifts in glucose control were consistent with class effect for first generation SRLs

• Mean serum glucose and HbA1c levels in patients with acromegaly receiving OOC treatment were consistent from baseline to EOT

Melmed, S. Endocrinol Metab Clin North Am. 2008 Mar; 37(1): 101–122, viii.

Glycemic control in patients receiving OOC treatment is consistent with the class effect observed in first generation injectable SRLs