FDA MEDICAL OFFICER REVIEW TARGRETIN (BEXAROTENE) 75mg

CAPSULES

LIGAND PHARMACEUTICALS INC.

AMY CHAPMAN PROJECT MANAGER OLUWOLE O. ODUJINRIN, MD MEDICAL JOHN JOHNSON MD MEDICAL MARK ROTHMANN Ph D BIOSTATISTICS GANG CHEN Ph D BIOSTATISTICS GENE WILLIAMS Ph D

BIOPHARMACEUTICS ATIQUR RAHMAN Ph D

BIOPHARMACEUTICS CHANG AHN Ph D PHARMACOLOGY PAUL ANDREWS Ph. D PHARMACOLOGY SUNG KIM Ph D CHEMIST REBECCA WOODS Ph D CHEMIST

REVIEW TEAM

GENERAL INFORMATION

Proposed Indication: Treatment of cutaneous manifestations in patients with all clinical stages (1A-IVB) of Cutaneous T-Cell Lymphoma (CTCL) in the following categories:

– patients with early stage CTCL who have not tolerated other therapies

– patients with refractory or persistent early stage CTCL– patients with refractory advanced stage CTCL.

PIVOTAL STUDIES PIVOTAL STUDY #1: Protocol # L1069-23

Title: A Multicenter International Phase 2-3 Evaluation of TARGRETINTM Capsules in Patients with Refractory or Persistent Early Stage Cutaneous T‑Cell Lymphoma

PIVOTAL STUDY #2: Protocol # L1069-24

Title: A Multicenter International Phase 2-3 Evaluation of TARGRETINTM Capsules in Patients with Refractory Advanced Stage Cutaneous T‑Cell Lymphoma

Physician's Global Assessment of Clinical Condition (PGA)

The Physician's Global Assessment is the Investigator’s assessment of the extent of improvement/worsening of the patient's overall disease compared to the condition at baseline.

Composite Assessment of Index Lesions (CA)

The summation of the grades for all index lesions for the following clinical signs:

erythema (Grade: 0-8), scaling (Grade: 0-8), plaque elevation (Grade: 0-8), hypopigmentation or hyperpigmentation (Grade: 0-

8), and index lesion area involvement (Grade: 0-18).

Primary Endpoint Classification of Response (PEC) The total response rate, considering

response according to EITHER PGA OR CA.

Secondary Efficacy Assessments

Time to Response Duration of Response Durability of Response Time to Disease Progression Total Body Surface Area involved Individual Index Lesions signs &symptoms Clinically abnormal nodes CTCL tumors present Visceral Involvement QOL Questionnaires

Photographic support of Primary and Secondary Efficacy Assessments Five (5) designated index lesions will be serially

photographed at baseline and every four (4) weeks thereafter for the duration of treatment. At the follow-up visit, these five index lesions must be photographed. Global photographs (half-body fields, anterior and posterior) of each patient’s CTCL disease will be obtained on Day 1 (baseline), every four (4) weeks during treatment and again at the patient’s follow-up visit. All index lesion and global areas which are photographed at baseline must be re-photographed every four (4) weeks, even if the lesions have cleared, until the patient completes the follow-up study visit.

FDA Evaluation of Study Results

Baseline Disease Characteristics(Early Disease)

Initial Assigned Dose (mg/m2/day)6.5

N = 15N (%)*

300N = 28N (%)

>300N = 15N (%)

All PatientsN = 58N (%)

Stage of CTCL 1 (A and B)II

13 (86.7%)2 (13.3%)

25 (89.3%)3 (10.7)

13 (86.7%)2 (13.3)

51 (87.9%)7 (10.3%)

Duration of CTCL1st ManifestationMean(in months)Min/Median/Max1st Path. DxMean(in months)

Min/Median/Max

157.960 / 134 / 316

95.9

5 / 75 / 206

150.424 / 120 / 588

102.7

0 / 85 / 588

184.529 / 156 / 706

116.9

13 / 84 / 314

161.224 / 126 / 706

101.0

0 / 79 / 588

Baseline Disease Characteristics(Advanced Disease)

Initial Assigned Dose (mg/m2/day)300

N = 56N (%)(2)

>300N = 38N (%)

All PatientsN = 94N (%)

Stage of CTCL IIBIIIIVAIVB

23 ( 41.1) 19 ( 33.9) 9 ( 16.1) 5 ( 8.9)

17 ( 44.7) 10 ( 26.3) 6 ( 15.8) 4 ( 10.5)

40 ( 42.6) 29 ( 30.9) 15 ( 16.0) 9 ( 9.6)

Duration of CTCL 1st ManifestationMean (in months)Min / Median / Max1st Path Dx Mean (in months) Min / Median / Max

121.39 / 102 / 372

60.41 / 42 / 336

102.613 / 84 / 324

64.5–1/ 41 / 220

113.79 / 88 / 372

62.0-1/ 41 / 336

Tumor Response Early DiseasePGA and CA

Dose 300 Dose 6.5

N CCR+PR(%)

CCR(%)

N CCR+PR(%)

CCR (%)

PGA(Lig)

43 23 (53) 3 (7) 15 1 (7) 0 (0)

PGA(Fda)

43 Not Reviewable Without Full Body Photographs

CA (Lig) 43 17(40) 4(10) 15 3(20) 1(7)CA (Fda) 43 15 (35) 3 (7) 15 3 (20) 1 (7)

BothPGA&CA

*

14

PGANot CA*

9

CA*Not PGA

3

* Using Ligand Response Assessments

Tumor Response Advanced Disease

PGA and CAN CCR+PR (%) CCR (%)

PGA (Lig) 94 47 (50) 2 (2)PGA (Fda) 94 Not Reviewable Without Full Body PhotographsCA (Lig) 94 33(35) 6(6)CA (Fda) 94 27 (29) 6 (6)

BothPGA&CA*

29

PGA NotCA*

18

CA NotPGA*

4

* Using Ligand Response Assessments

Secondary Efficacy Results FDA findings are generally similar to those of the sponsor

in terms of: Duration of Response Time to Disease Progression

Results should be interpreted with these considerations: Lack of control group creates difficulty in establishing true treatment

effect. Short study duration with many patients censored for Time to events Reliable Time to event estimates are difficult to make. Potential for large margin of error

Kaplan-Meier curves are exploratory.

Secondary Efficacy Criteria Total Body Surface Area involved

% BSA Tumor Involvement Dose 300mg/m2/day

EARLY DISEASE

ADVANCED DISEASE

NResponse(%)

N Response(%)

BSA 43 16 (37) 94 31 (33)Both BSA&PGA 16 29BSA Not PGA 0 2PGA Not BSA 7 18

Secondary Efficacy Criteria QOL Questionnaires

Unexplained discrepancy between results of the Ligand developed CTCL specific Global QOL and the Spitzer Global QOL questionaires. Worsening on Spitzer Global

QOL, but good improvement on the CTCL specific Global QOL assessment.

Secondary Efficacy Criteria(Others)

Individual Index Lesions signs &symptoms Pigmentation: Very few patients had baseline pigmentary changes

in both studies. Pruritus: No clinically significant change from baseline in patients

taking and not taking antipruritics, in both studies.

Clinically abnormal nodes 8/58( 14%) patients in early disease. No change with treatment. 38/94 (40%) patients in advanced disease. 3 patients had a complete or

>50% reduction in the number and aggregate area of positive nodes

Pathologically positive lymph nodes. No patient with pre-study to post-baseline data

Secondary Efficacy Criteria(Others)

CTCL tumors present 33/94 (35%) patients . 1 patient had complete resolution of tumor

Visceral Involvement No demonstrated response in visceral disease was noted in this

study. Sezary Cells:

No uniform method of evaluation; microscopic vs flow-cytometry 6 patients had pre- and at least one post baseline evaluation. 2 had

improvement in counts. 2 had rising counts while experiencing improving index skin lesions.

SAFETY

FDA generally agrees with Ligand’s findings of safety profile in both protocols :

At least one AE: – 97% of patients in protocol #1– 99% of patients in protocol #2

Numerous lab. abnormalities and AEs. The most frequent were:

Hypertriglyceridemia (78%) Hypothyroidism (38%) Asthenia (30%)

Serum Triglycerides

Triglyceride levels of >800mg/dl were seen in 32/58 (55%) patients in early disease and 53/94 (56%) patients with advanced disease.

Triglyceride increase occurred within 2 to 4 weeks of initiating targretin treatment, and persisted over 400mg/dl for 4-6 weeks with management.

78% of patients with advanced disease and 62% overall required anti-lipemic therapy.

High lipid values were associated with clinical complications: Pancreatitis and other gastrointestinal complaints.

Clinical Morbidity from AE Pancreatitis documented with serum

amylase in 4 patients. Abdominal symptoms without serum

amylase in 4 other patients. Coronary Heart Disease requiring bypass

surgery in 1 patient. Acute MI resulting in death of 1 patient Congestive heart failure resulting in death

of 1 other patient

Clinical morbidities.

Cataracts:10/47(21%) patients having serial slit-lamp eye exam had new or worsening cataract.

Hepatic hemorrhage resulting in death of 1 patient. Quality of Life issues.

– Need for numerous medications– Increased risk of drug-drug interactions– Morbidity from hypothyroidism, anemia– Need for antipruritics continue for most patients.

Quality of study Data Numerous amendments to original protocol Numerous protocol violations.75% and 90% respectively

had at least one protocol violation. Excessive patient withdrawal due to AEs.

– 30% in L1069-23 and 35% in L1069-24 Too few patients in some patient subsets for any

meaningful conclusions to be drawn; e.g 6.5mg/m2 dose group, both pre and post-cross-over.

Some patients were not refractory, reached a plateau, or had progressive disease on prior therapy:

– Pt#541 received methotrexate for 3 months (5/15/97-8/15/97), entered on study on 9/5/97.Was having PR(>50%) on MTX. No evidence of progression. Uncertainties about other therapies.

Quality of study Data

Some patients were still within the washout period of their prior therapy at enrollment on study.

– Pt #1474 on Acutane within 30 days of study entry. “Written waiver” given to Investigator by Ligand. Pt had improvements in cutaneous lesion, Sezary counts and prolonged PGA and CA (190 days*) responses

– Pt #143 on Interferon 21 days before study entry. A Ligand PR by CA and PGA at cross-over after day 37.

– Pt# 1475 on CMED chemotherapy within 4 weeks of study entry. The 2nd patient with improvement in Sezary count. A Ligand PGA not CA responder

– Pt#443 “With permission from Ligand patient entered after only 2.5 week wash-out from last PUVA.” Investigator CRF entry. Pt was a Ligand PGA responder.

PHOTOGRAPHS

Photographic issues

Applicant did not fully comply with protocol requirements.

FDA therefore can not assess the sponsor’s claimed responses on the PGA.

Some of the photographs suggest significant differences in responses claimed by the applicant.

RISK/ BENEFIT ISSUES

Issues for Consideration What has the sponsor shown to be the apparent benefit to

patients given Targretin therapy? Has the benefit been shown in the intended patient

population? How well defined is the population regarding

refractoriness to prior anti-CTCL therapy; in terms of therapies selected for this study, and others not included as requirements?

What is the size of the benefit and how credible is the evidence of benefit?

How well have the efficacy instruments assured confidence in the results reported?

Potential Benefits of Targretin Treatment.

BSA reduction by 37% and 33%of patients Demonstrable improvement in other index skin

lesions in approximately 30% of patients with early and moderately advanced disease.

Actual duration of the improvement is however uncertain from these studies.

Uncertain if patient population is truly refractory to prior therapies indicated for entry on this study

Oral medication

Risk/Benefit Considerations

Treatment alternatives Oral agents: Chlorambucil (often with prednisone)

• Etoposide• Cyclophosphamide

Intravenous Therapy: Single Agent: Fludarabine, Pentostatin, Cyclosporine (in severe

cases)• High dose MTX -LV

Combination therapy (Bunn et al Ann Int. Med.,1994 ): Cytoxan, Adriamycin, Etoposide, Vincristine.(81% RR, 38% CR, 5 to 41month remission duration in 331 patients.)

– Other combination therapies in summary table

SINGLE AGENT CHEMOTHERAPY FOR ADVANCED (STAGE II-IV) M.F. and SEZARY SYNDROME

Patients CR or PR CR Response DurationAuthor TherapyN N(%) N(%) Months

Winkleman et al. Chlorambucil+Prednisone

21 11 (57) 3 (14) NR

Bunn et al. rIFN2 20 9(45%) 3(15 6Kaplan et al. rIFN 16 5(31) 0(0) 10Grever et al. DCF 18 6(33) 2(11) 8Saven et al. 2-CDA 15 7(47) 3(20) 5Von Hoff et al. FAMP 31 6(19) 1(3) NRMolin et al. 13 cis-retinoic

acid39 23(59) 8(21) 4

Molin Etretinate 29 16(67) 5(21) 3Bunn et al. Single Agents 526 329(62) 91(33) 3-22

Risks of Targretin therapy

62% of the patient population had to take supplemental antilipemic drug treatment.

43% of patients had to take supplemental thyroid medication.

There are cardiac, GI and other complications resulting from high lipid levels.

Targretin may complicate many medical problems of the

elderly; diabetes, cataracts, asthenia etc.

Risk/ Benefit Issues Elderly patient population. CTCL is an extremely indolent but bothersome chronic illness.

A study patient lived with this illness for 59 years, and another for 52years before study entry.

What are the alternatives?– Issues of refractoriness to existing therapies.– Issues of study design.

Is the benefit derived from Targretin high enough to ask a patient to live with its not so trivial complications?

CONCLUSIONS

In the context of the study design, Targretin does have activity in this disease. The activity is exclusively cutaneous.

Degree of activity and duration of the activity are however not

overwhelming. In the absence of a comparator, it is difficult to determine the true

effect size of targretin viz-a-viz other existing and less onerous therapies.

There were many flaws in the execution and reporting of these studies.

There are serious and significant safety issues with the use of Targretin capsule therapy.

CONCLUSIONS

Uncertain if patient population is truly refractory to prior therapies indicated for entry on this study.

It is certain that enrolled patients have not exhausted the plethora of available therapies to patients with CTCL, hence cannot be considered a unique population for whom no alternatives exist.

Patients enrolled in both studies mostly represent groups with less aggressive disease (87.9% stage I in early disease protocol and 73.5% of patients were stage II or III in the advanced disease protocol).

The FDA is unable to confirm the claimed PGA tumor

responses in the absence of protocol stipulated

photographic requirements.

FDA APPROVED DRUGS FOR CTCL (Manufacturer)

Cortone Acetate tablets and Injectable Suspension (Merk) Decadron Tablets and Decadron Phosphate Injection (Merk) Cytoxan Tablets and Injection (Bristol-Meyer Squibb

Oncology/Immunology) Methotrexate Sodium Tablets and Injection (Immunex) Mustargen for Injection (Merk) Velban Vials (Lilly) 8-MOP Capsules (ICN) Ontak Vials (Ligand)