Drug Trials Snapshot: PONVORY

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The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the PONVORY Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

PONVORY (ponesimod)
(Pon-VOR-ee)
Janssen Pharmaceuticals, Inc.
Approval date: 03/18/2021

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

PONVORY is a prescription medicine that is used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

In relapsing forms of MS, patients have episodes of worsening function (relapses) followed by recovery periods. Patients can also experience an increase in the underlying disability, particularly as the disease progresses.

How is this drug used?

PONVORY is provided as a 14-day starter pack of tablets. The dose must be slowly increased over the first two weeks. PONVORY is then taken once daily at a dose of 20 mg starting on Day 15.

What are the benefits of this drug?

PONVORY was better in reducing the risk of disease relapse in comparison to teriflunomide, a product approved for the treatment of relapsing forms of MS.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the evaluated patients from Trial 1. The primary endpoint was the annualized relapse rate (ARR). Additional outcome measures included: 1) the number of new or enlarging MRI T2 hyperintense lesions per year, 2) the number of MRI T1 Gadolinium-enhancing lesions at scheduled study visits, and 3)Disability progression defined as 1.5 point increase in EDSS for patients with a baseline EDSS score of 0, 1.0 point increase in EDSS for patients with a baseline EDSS score of 1.0 to 5.0, or 0.5 point increase in EDSS for patients with a baseline EDSS score at least 5.5 confirmed 3 months later. The number of patients representing efficacy findings may differ from the number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety.

Table1: Clinical and MRI Endpoints from Trial 1

Endpoints	PONVORY 20 mg N =567	Teriflunomide 14 mg N =566
Clinical Endpoints
Annualized Relapse Ratea	0.202	0.290
Relative reduction	30.5% (p=0.0003)
Percentage of patients without relapseb	70.7%	60.6%
Proportion of Patients with 3-month Confirmed Disability Progressionc	10.8%	13.2%
Hazard Ratiod	0.83 (p=0.29)e
MRI Endpointsb, f
Mean number of new or enlarging T2 hyperintense lesions per year	1.40	3.16
Relative reduction	55.7% (p <.0001)
Mean number of T1 Gd-enhancing lesions per MRI	0.18	0.43
Relative reduction	58.5% (p <.0001)

Source: PONVORY Prescribing Information
^a Defined as confirmed relapses per year through the study period (Negative binomial regression model with stratification variables (EDSS ≤ 3.5 versus EDSS > 3.5; non-steroid treatment for MS within last 2 years prior to randomization [Yes/No]) and the number of relapses in the year prior to study entry (≤1, ≥2) as covariates)
^b Over the study period of approximately 108 weeks
^c Disability progression defined as 1.5 point increase in EDSS for patients with a baseline EDSS score of 0, 1.0 point increase in EDSS for patients with a baseline EDSS score of 1.0 to 5.0, or 0.5 point increase in EDSS for patients with a baseline EDSS score at least 5.5 confirmed 3 months later. Proportion of patients with 3 month confirmed disability progression refers to Kaplan-Meier estimates at Week 108.
^d Defined as time to 3 months confirmed disability progression through the study period (Stratified Cox proportional hazard model, p-value based on the stratified log rank test)
^e Not statistically significant
^f Cumulative number of combined unique active lesions (CUALs), defined as new or enlarging T2 lesions or Gd enhancing T1 lesions (without double counting), mean lesions per year were 1.41 on PONVORY 20 mg (N=539), and 3.16 on teriflunomide 14 mg (N=536), a relative reduction of 56% (p<0.0001).

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

• Sex: PONVORY worked similarly in males and females
• Race: The number of patients of races other than White was small; therefore, differences in how well PONVORY worked among races could not be determined.
• Age: PONVORY worked similarly in patients below and above 40 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes efficacy results by age and sex from Trial 1. Analysis by race was not performed because almost all patients were White.

Table 2: Subgroup Analysis of ARR by Sex and Age

	PONVORY 20 mg (n=567)	Teriflunomide 14 mg (n=566)	% ARR reduction
Age
< 40 years	0.236	0.335	29.6%
≥ 40 years	0.184	0.255	27.8%
Sex
Female	0.211	0.305	30.8%
Male	0.226	0.298	24.2%

Source: FDA Review

What are the possible side effects?

PONVORY may cause serious side effects including life threatening infections, decreased heart rate, liver injury, increased blood pressure, decreased lung function, and build-up of fluid in the back of the eye (macular edema).

The most common side effects of PONVORY are upper respiratory infections, increased liver enzymes, and high blood pressure.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in patients with relapsing forms of MS in the clinical trial. Number of patients representing efficacy findings may differ from number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety.

Table 3: Adverse Reactions with an Incidence of at Least 2% of PONVORY Treated Patients and at a Higher Rate Than in Patients Receiving Teriflunomide 14 mg in Trial 1

Adverse Reaction	PONVORY 20 mg N=565 (%)	Teriflunomide 14 mg N=566 (%)
Upper respiratory infection a	37	34
Hepatic transaminase elevation b	23	12
Hypertension c	10	9
Urinary tract infection	6	5
Dyspnea	5	1
Dizziness	5	3
Cough	4	2
Pain in extremity	4	3
Somnolence	3	2
Pyrexia	2	1
C-reactive protein increased	2	1
Hypercholesterolemia	2	1
Vertigo	2	1

Source: Ponvory Prescribing Information
^a Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, respiratory tract infection viral, viral upper respiratory tract infection, tracheitis, and laryngitis.
^b Includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased.
^c Includes the following terms: hypertension, hypertensive crisis, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased.

Were there any differences in side effects of the clinical trials among sex, race, and age?

• Sex: The occurrence of side effects was similar in males and females.
• Race: The number of patients of races other than White was small; therefore, differences in the occurrence of side effects among races could not be determined.
• Age: The occurrence of side effects was similar in patients below and above 40 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The tables below summarize the occurrence of the most common adverse events in PONVORY-treated patients by sex and age subgroups. Analysis by race was not performed because almost all patients were White. Presented data are from the safety population that includes PONVORY-treated patients from Trial 1.

Table 4: Common Adverse Events by Sex in Patients Treated with PONVORY in Trial 1

Adverse Reactions	Female n=363	Male N=202
Nasopharyngitis	107	63
Alanine aminotransferase increased	91	73
Headache	75	24
Upper respiratory tract infection	61	31
Nausea	45	8
Hypertension	37	13
Back pain	28	12
Urinary tract infection	37	3
Aspartate aminotransferase increased	22	16
Fatigue	28	10
Oral herpes	34	3
Dyspnea	20	15
Dizziness	27	6
Bronchitis	19	13
Respiratory tract infection viral	19	12
Influenza	12	15
Hepatic enzyme increased	11	15
Cough	14	10
Depression	14	9
Pain in extremity	17	6
Abdominal pain upper	12	10
Diarrhea	17	4
Respiratory tract infection	16	4
Alopecia	17	2
Hyperkalemia	9	10
Anxiety	14	4
Arthralgia	10	8
Somnolence	11	7
Constipation	10	7
Hypoesthesia	13	4
Paresthesia	13	4
Pharyngitis	12	5
Herpes zoster	12	4
Anemia	15	0
Hypercholesterolemia	9	6
Rhinitis	11	4
Dyspepsia	6	8
Abdominal pain	10	3
Gastroenteritis	10	3
Vertigo	12	1
Viral infection	7	6
Vomiting	10	3
Asthenia	6	6
C-reactive protein increased	6	6
Pyrexia	8	4
Transaminases increased	6	6
Viral upper respiratory tract infection	7	5
Fall	7	4
Insomnia	6	5
Musculoskeletal pain	6	5
Sinusitis	9	2
Tonsillitis	6	5
Blood pressure increased	8	2
Lymphopenia	10	0

Source: FDA Review

Table 5: Common Adverse Events by Age Group in Patients Treated with PONVORY in Trial 1

Adverse Reactions	Age < 40 n=349	Age ≥ 40 N=216
Nasopharyngitis	125	45
Alanine aminotransferase increased	122	42
Headache	50	49
Upper respiratory tract infection	51	41
Nausea	36	17
Hypertension	19	31
Back pain	22	18
Urinary tract infection	18	22
Aspartate aminotransferase increased	25	13
Fatigue	27	11
Oral herpes	32	5
Dyspnea	23	12
Dizziness	17	16
Bronchitis	25	7
Respiratory tract infection viral	21	10
Influenza	18	9
Hepatic enzyme increased	10	16
Cough	14	10
Depression	13	10
Pain in extremity	8	15
Abdominal pain upper	15	7
Diarrhea	6	15
Respiratory tract infection	10	10
Alopecia	13	6
Hyperkalemia	13	6
Anxiety	8	10
Arthralgia	9	9
Somnolence	14	4
Constipation	9	8
Hypoesthesia	8	9
Paresthesia	9	8
Pharyngitis	10	7
Herpes zoster	10	6
Anemia	10	5
Hypercholesterolemia	9	6
Rhinitis	13	2

Source: FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved PONVORY based on evidence from a clinical trial (Trial 1/ NCT02425644) of 1133 patients with relapsing forms of multiple sclerosis. The trial was conducted at 162 sites in 28 countries in North America, Europe, Mexico, Israel, and Turkey.

Figure 1 summarizes how many men and women were enrolled in the clinical trial used to evaluate the efficacy of PONVORY.

Figure 1. Baseline Demographics by Sex (Efficacy Population)

Source: FDA Review

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy of PONVORY.

Figure 2. Baseline Demographics by Race (Efficacy Population)

Source: FDA Review

Figure 3. Baseline Demographics by Age (Efficacy Population)

Source: FDA Review

Who participated in the trials?

The table below summarizes the demographics of the safety population in Trial 1.

Table 6: Demographics of Patients in Trial 1

Demographic Parameter	Ponesimod 20 mg n=567	Teriflunomide 14 mg n=566
Age (years)2
Mean (SD)	36.7 (8.7)	36.8 (8.7)
Median	36	37
Min, Max	18, 55	18, 55
≤40 years	372 (65.8%)	365 (64.5%)
> 40	193 (34.2%)	201 (35.5%)
Sex
Female	363 (64.2%)	372 (65.7%)
Male	202 (35.8%)	194 (34.3%)
Race
White	549 (97.2%)	553 (97.7%)
Black or African	3 (0.5%)	2 (0.4%)
Unknown / Other	13 (2.3%)	11 (1.9%)
Ethnicity
Not Hispanic or Latino	524 (92.7%)	528 (93.2%)
Hispanic or Latino	27 (4.8%)	23 (4.1%)
Not reported / Unknown	14 (2.5%)	15 (2.7%)

Sopurce: FDA Review

How were the trials designed?

The benefits and side effects of PONVORY were evaluated in a clinical trial of patients with relapsing forms of MS. Patients received PONVORY or comparator for up 2 years. Neither the patients nor the health care providers knew which treatment was being given until the trials were completed.

The benefit of PONVORY was evaluated based on the percentage of patients who experienced reduction in disease relapse in comparison to patients treated with teriflunomide.

How were the trials designed?

The safety and efficacy of PONVORY were established in a randomized, double-blind, double-dummy, active comparator-controlled clinical trial. The trial included patients with relapsing forms of multiple sclerosis (MS). Patients were randomized to receive either PONVORY 20 mg given orally once daily, beginning with a dose titration, or teriflunomide, 14 mg given orally daily. Patients in Trial 1 were treated for 2 years.

The primary endpoint was the annualized relapse rate (ARR) during the treatment period. Key secondary endpoints include the change in MS fatigue (as measured by the Fatigue Severity Impact Scale – Relapsing Multiple Sclerosis [FSIQ-RMS]), an MRI metric (combined unique active lesions [CUAL]) which included new T1 Gadlinium-enhancing lesions and new/enlarging T2 lesions, and confirmed disability accumulation (CDA) at 3 and at 6 months.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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