213176Orig1Orig2s000

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

PRODUCT QUALITY REVIEW(S)

OPQ-XOPQ-TEM-0001v04 Page 1 of 2 Effective Date: 14 February 2017

QUALITY ASSESSMENT

Recommendation: APPROVAL

NDA 213176

Review #1

Drug Name/Dosage Form

Umbralisib Tablets

Strength

200 mg

Route of Administration

Oral

Rx/OTC Dispensed

Applicant

TG Therapeutics, Inc

US agent, if applicable

n/a

SUBMISSION(S)

REVIEWED

DOCUMENT

DATE

DISCIPLINE(S) AFFECTED

Original Submission

1/10/2020

All

Amendment (SD)

01/24/2020

Process/Facilities

Amendment (SD)

01/27/2020

Amendment (SD)

02/03/2020

DS, Process/Facilities

Amendment (SD)

03/05/2020

DP, DS

Amendment (SD)

03/19/2020

DP, DS

Amendment (SD)

04/14/2020

DP, DS

Amendment (SD)

04/17/2020

Amendment (SD)

06/15/2020

Process/Facilities

Amendment (SD)

07/07/2020

Amendment (SD)

07/13/2020

Amendment (SD)

07/14/2020

DS, Process/Facilities

Amendment (SD)

07/21/2020

DS, Biopharm

Amendment (SD)

09/11/2020

Process/Facilities

Quality Review Team

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v04 Page 2 of 2 Effective Date: 14 February 2017

QUALITY ASSESSMENT

DISCIPLINE

PRIMARY REVIEWER

SECONDARY REVIEWER

Drug Master File/Drug

Substance

Kabir Shahjahan

Ali Al Hakim

Drug Product

Yang Nan

Anamitro Banerjee

Process and Facilities

Byeongtaek Oh

Bogdan Kurtyka

Microbiology

n/a

Biopharmaceutics

Qi Zhang

Om Anand

Regulatory Business

Process Manager

Rabiya Haider

n/a

Application Technical Lead

Sherita McLamore

n/a

Laboratory (OTR)

n/a

Environmental

Yang Nan

Anamitro Banerjee

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v04 Page 1 of 1 Effective Date: 14 February 2017

QUALITY ASSESSMENT

Quality Review Data Sheet

1. RELATED/SUPPORTING DOCUMENTS

A. DMFs:

DMF # Type Holder Item Referenced

Status

Date Review

Completed

Comments

Type

III

n/a

No Review

Adequate

information

provided in

the NDA

Type

III

n/a

No Review

Adequate

information

provided in

the NDA

Type

III

n/a

No Review

Adequate

information

provided in

the NDA

B. Other Documents: IND, RLD, or sister applications

DOCUMENT APPLICATION NUMBER DESCRIPTION

IND

116762

Development of umbralisib tosylate

IND

Development of umbralisib tosylate

IND

Development of umbralisib tosylate

2. CONSULTS

N/A

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v04 Page 1 of 5 Effective Date: 14 February 2017

QUALITY ASSESSMENT

Executive Summary

I. Recommendations and Conclusion on Approvability

OPQ recommends APPROVAL of NDA 213176 UKONIQ (umbralisib) tablets, 200 mg.

As part of this action, OPQ grants a 36-month expiration period for the drug product

when stored at “20°C to 25°C (68°F to 77°F) excursions permitted between 15°C to 30°C

(59°F to 86°F) [see USP controlled room temperature].” There are no outstanding issues

and no post-approval quality agreements to be conveyed to the applicant.

II. Summary of Quality Assessments

A. Product Overview

NDA 213176 was submitted for UKONIQ (umbralisib) tablets, 200 mg in accordance

with section 505(b)(1) of the Food, Drug and Cosmetic Act. Umbralisib is a once daily,

orally bioavailable dual inhibitor of phosphoinositide-3‐kinase (P13K) delta and casein

kinase 1 epsilon (CK1ε) that is indicated for the treatment of marginal zone lymphoma

(MZL) who have received at least one prior anti-CD20-based regimen and for relapsed or

refractory Follicular Lymphoma (FL) who have received at least prior systemic

therapies. Umbralisib is an NME that was granted Orphan Designation for the treatment

of nodal, splenic and extranodal marginal zone lymphoma (MZL) (March 2016) and

Breakthrough Therapy Designation for MZL (January 17, 2019. The applicant was

granted a rolling review and requested accelerated approval for treatment of adult patients

with:

•Marginal Zone Lymphoma (MZL) who have received at least one prior anti

CD20-basedregimen.

•Relapsed or refractory Follicular Lymphoma (FL) who have received at least

prior systemic therapies

Umbralisib tosylate is a small chiral BCS class II molecule that is produced as a single

enantiomer that is manufactured by Alembic Pharmaceuticals Limited, India as a single

enantiomer in a linear, two-stage synthesis. The drug product is presented as a 200 mg

immediate-release, tablet for oral administration. It is a green film-coated, oval-shaped

tablet, debossed with “L474” on one side and plain on the other.

The recommended starting dose for the drug product is 800 mg orally, once daily until

disease progression or unacceptable toxicity.

Based on the information provided in this application (original submission and in

responses to information requests), OPQ considers all review issues adequately addressed

and potential risks to patient safety, product efficacy, and product quality mitigated

appropriately. Accordingly, OPQ recommends APPROVAL of NDA 213176 and grants

a month retest for the drug substance and a 36-month shelf-life for the drug product

when stored in HDPE bottles at 20ºC to 25ºC (68ºF to 77ºF).

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v04 Page 2 of 5 Effective Date: 14 February 2017

QUALITY ASSESSMENT

Proposed Indication(s) including

Intended Patient Population

Indicated for the treatment of adult patients with

marginal zone lymphoma (MZL) who have received at

least one prior anti-CD20-based regimen

Duration of Treatment

until disease progression or until unacceptable toxicity.

Maximum Daily Dose

800 mg

Alternative Methods of

Administration

None

B. Quality Assessment Overview

Drug Substance

Umbralisib tosylate is a small chiral BCS class II molecule that is manufactured as a

single enantiomer. It is freely soluble in dimethyl sulfoxide, soluble in methanol, and

practically insoluble in water.

Umbralisib tosylate drug substance is synthesized by

Alembic Pharmaceuticals Limited at a typical batch size of

The proposed commercial synthesis the fourth-generation process used through its

development; however, the overall manufacturing route and intermediates remained

unchanged in all generations.

The drug substance manufacturing process is described in sufficient detail

. The applicant provided adequate justification for the

suitability of the proposed control strategy for the drug substance manufacturing

process. The drug substance was investigated for polymorphism and the data indicated

that umbralisib tosylate does not exhibit polymorphic behavior

The drug substance is stored

the specifications and

acceptance criteria for the drug substance are consistent with ICH Q6A and are

adequate to ensure the quality of the drug substance as it relates to the safety and

efficacy of the drug product. The applicant proposed acceptance criterion of ≤

, which is not listed in ICH Q3C. Based on informal consult with

pharm/tox reviewer Dr. Simon Williams, the OPQ review team concluded that the

proposed limit is acceptable. All analytical methods are described in adequate

detail and are appropriate for their intended use. All validation parameters - system

suitability and system precision, specificity, linearity, range, precision, accuracy,

ruggedness, robustness, and stability of solutions are provided in the NDA.

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v04 Page 3 of 5 Effective Date: 14 February 2017

QUALITY ASSESSMENT

Batch analyses were included for sixty-two drug substance batches. All batches were

within the proposed specification and are acceptable.

The applicant provided up to 24 months of long term (25℃/60%RH) and 6-month

accelerated (40℃/75%RH) stability data for three registration batches of the drug

substance. Thirty-six months of long-term data was also provided for one supportive

drug substance batch. The stability data for the registration batches demonstrated no

notable changes after up to 24 months under long term storage condition. The applicant

requested month retest for drug substance. The provided stability data and stress

testing supports the proposed retest of months for the drug substance

and may be granted.

Drug Product

The drug product, UKONIQ (umbralisib) tablets, 200 mg, is an immediate-release,

non-enteric, film-coated tablets for oral administration. The drug product formulation

includes the active (200 mg umbralisib free base, equivalent to 260.20 mg umbralisib

tosylate) together with compendial excipients that are commonly used in solid oral

dosage forms (hydroxypropyl betadex, croscarmellose sodium, microcrystalline

cellulose, hydroxypropyl cellulose, magnesium stearate, and ). The

tablet coating contains Hypromellose 2910 , titanium

dioxide, triacetin, polydextrose, PEG 8000, FD&C Yellow, FD&C Blue and

iron oxide. The drug product is presented as a green film-coated, oval-shaped tablet,

debossed with “L474” on one side and plain on the other. The formulation contains no

novel excipients and each of the excipients are below the maximum potency as

reported in the IIG. Detailed descriptions of the quantitative and qualitative drug

product formulation are provided in the submission.

The drug product is manufactured by Alembic Pharmaceuticals Ltd, of India at a

commercial batch size of which corresponds to tablets. The drug

product manufactured

standard processing equipment with clearly defined CPPs and IPCs. The applicant

demonstrated the suitability of the manufacturing process for the drug product at the

proposed commercial scale. The description of the manufacturing process includes

appropriate in-process controls and operating parameters and is described in sufficient

detail to support the approval of this NDA.

The drug product specifications include appearance, identification, uniformity of

dosage units, assay, related substances, dissolution, microbial limits .

The applicant included a risk assessment for elemental impurities as per ICH Q3D/USP

<232> and provided justification for the omission of tests for residual solvents

(complies with USP<467> option 1). The results of the risk assessment were

acceptable and therefore a test for an elemental impurity in the drug product release

specifications was not proposed and is not required. The final drug product

specifications are consistent with ICH Q6A and are based on batch analyses,

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v04 Page 4 of 5 Effective Date: 14 February 2017

QUALITY ASSESSMENT

manufacturing capability, and stability data. The drug product specifications are

adequate to establish the drug product identity, potency and purity and provide

adequate controls to ensure the quality of the drug product through the product expiry.

The proposed specifications and acceptance criteria for the drug product, together with

controls for impurities in the drug substance are adequate to ensure that the critical

quality attributes of this product are well controlled.

In support of the proposed 36-month expiry, the applicant included 24 months of long

term (25°C/60% RH) and 6 months of accelerated (40°C/75% RH) data for three

commercial scale batches of the drug product packaged in the intended commercial

packaging (120-count white opaque round 150 cc HDPE bottles with a 38 mm

polypropylene cap with a heat seal peelable foil liner). All primary stability batches

were manufactured at the commercial site according to the proposed commercial

manufacturing process. Stability studies were executed in accordance with the ICH 1A

and Q1B; and the available stability data shows consistency over time and supports the

proposed expiry. Therefore, based on the 24 months of primary stability data and the

supportive stability data included in this application for UKONIQ (umbralisib) tablets,

200 mg, TG Therapeutics, Inc proposed and the FDA accepts the expiration dating

period of 36 months for the drug product when stored at controlled room temperature

20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to

86°F).

NDA 213176 is recommended for approval from a drug product and drug process

perspective.

Biopharmaceutics

The biopharmaceutics review focused on the acceptability of the proposed in vitro

dissolution method and acceptance criterion for the routine quality control testing of

the proposed drug product at batch release and on stability. The dissolution method

included a USP Apparatus 1 (Baskets, 10 mesh) at 100 RPM in 900 mL of 0.05M

Phosphate Buffer with 0.5% sodium lauryl sulfate at 37°C. The proposed dissolution

acceptance criterion was Q % in 45 minutes. The dissolution method and

acceptance criterion are acceptable as QC method for batch release and stability testing

of the drug product.

The proposed to-be-marketed Umbralisib Tablets, film coated, 200 mg have the same

formulation and manufacturing site as the batches used in the pivotal clinical study.

Accordingly, bridging between the clinical formulation and commercial product was

not needed.

NDA 213176 is recommended for approval from biopharmaceutics perspective.

Facilities

This application includes 4 sites and all sites were listed as ready for inspection:

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v04 Page 5 of 5 Effective Date: 14 February 2017

QUALITY ASSESSMENT

 Alembic Pharmaceuticals Limited (API Unit-III) (FEI 3007501748)- Manufacture,

release and stability testing of umbralisib tosylate

 Alembic Pharmaceuticals Limited (Formulation Division) (FEI 3004956904) –

Testing of umbralisib tosylate for elemental impurities, manufacture of umbralisib

tablets, testing and release of umbralisib tablets, packaging of umbralisib tablets

 Packaging of umbralisib tablets

 TG Therapeutics, Inc. (FEI NOT LISTED)- Lot release for umbralisib tablets

All facilities were deemed acceptable for the responsibility listed in the application.

NDA 213176 is recommended for approval from the facilities perspective.

Environmental Assessment

The applicant provided a claim for categorical exclusion and a statement of no

extraordinary circumstances under 21 Code of Federal Regulations (CFR) Sections

25.31(e) and a statement of no extraordinary circumstances 21 CFR 25.15(d).

The request for categorical exclusion is granted.

C. Special Product Quality Labeling Recommendations (NDA only)

n/a

D. Final Risk Assessment (see Attachment)

Included at the beginning of the drug product review.

Reference ID: 4715049

(b) (4)

Sherita

McLamore

Digitally signed by Sherita McLamore

Date: 11/30/2020 02:47:13PM

GUID: 503257950000415755492db5bb8b1a5c

Reference ID: 4715049

63 Pages have been Withheld in Full as B4 (CCI/TS)

Immediately Following this Page

OPQ-XOPQ-TEM-0001v06

Page 1

Effective Date: February 1, 2019

CHAPTER IV: LABELING

IQA NDA Assessment Guide Reference

1.0 PRESCRIBING INFORMATION

Assessment of Product Quality Related Aspects of the Prescribing

Information:

1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION

Item

Information Provided

in the NDA

Assessor’s Comments

Product Title in Highlights

Proprietary name

UKONIQ

Adequate

Established name(s)

Umbralisib

Adequate

Route(s) of administration

Oral

Adequate

Dosage Forms and Strengths Heading in Highlights

Summary of the dosage

form(s) and strength(s)

in metric system.

Tablets: 200 mg

Adequate

Assess if the tablet is

scored. If product meets

guidelines and criteria for a

scored tablet, state

“functionally scored”

N/A

The drug product tablets are not

scored.

For injectable drug

products for parental

administration, use

appropriate package type

term (e.g., single-dose,

multiple-dose, single-

patient-use). Other

package terms include

pharmacy bulk package

and imaging bulk package.

N/A

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v06

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Effective Date: February 1, 2019

1.2 FULL PRESCRIBING INFORMATION

1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)

Item

Information Provided

in the NDA

Assessor’s Comments

DOSAGE AND ADMINISTRATION section

Special instructions for

product preparation (e.g.,

reconstitution and resulting

concentration, dilution,

compatible diluents,

storage conditions needed

to maintain the stability of

the reconstituted or diluted

product)

The drug product is tablet, no

special instruction for product

preparation is needed.

1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)

Item

Information

Provided

in the NDA

Assessor’s Comments

DOSAGE FORMS AND STRENGTHS section

Available dosage form(s)

Tablet

Adequate

Strength(s) in metric system

200 mg

Adequate

If the active ingredient is a salt,

apply the USP Salt Policy per FDA

Guidance

Refer to section 11.

A description of the identifying

characteristics of the dosage

forms, including shape, color,

coating, scoring, and imprinting

UKONIQ is a green,

film-coated, oval-

shaped, 200-mg

tablet

with “L474” on one

side and plain on

the other.

Adequate

Assess if the tablet is scored. If

product meets guidelines and

criteria for a scored tablet, state

“functionally scored

”

N/A

For injectable drug products for

parental administration, use

appropriate labeling term (e.g.,

single-dose, multiple-dose, single-

patient-use).

Other package type

terms include pharmacy bulk

N/A

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v06

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Effective Date: February 1, 2019

1.2.3 Section 11 (DESCRIPTION)

package and imaging bulk

package.

Item

Information Provided

in the NDA

Assessor’s Comments

DESCRIPTION section

Proprietary and established

name(s)

UKONIQ (umbralisib)

Adequate

Dosage form(s) and route(s)

of administration

UKONIQ tablets are for

oral administration.

Adequate

If the active ingredient is a

salt, apply the USP Salt

Policy and include the

equivalency statement per

FDA Guidance.

Each tablet contains 200

mg of umbralisib free

base equivalent to 260.2

mg of umbralisib tosylate

with the following inactive

ingredients:

microcrystalline cellulose,

hydroxypropyl betadex,

croscarmellose sodium,

hydroxypropyl cellulose,

magnesium stearate,

titanium dioxide,

polydextrose,

hypromellose 2910,

triacetin, FD&C Blue no.

1, polyethylene glycol

8000, FD&C yellow no. 5,

and ferric oxide yellow.

The active ingredient is a

tosylate salt, 200 mg is the

amount of free base. The

naming practice for the

strength 200 mg follows the

USP Salt Policy per FDA

Guidance. This is

adequate.

List names of all inactive

ingredients. Use USP/NF

names. Avoid Brand names.

See above

Compendial excipient

names follow USP/NF.

The drug product coating

film

contains FD&C Yellow No.

5. Email was sent on

September 25, 2020 to

clinical division about

specific warnings for this

excipient per 21 CFR

201.20 and warning

language is included in the

labeling.

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v06

Page 4

Effective Date: February 1, 2019

The excipients used in

tablets and those in coating

film

should be separated and

organized alphabetically.

Recommend Applicant to

revise the excipients as

follows:

Each tablet contains 200 mg

of umbralisib free base

equivalent to 260.2 mg of

umbralisib tosylate. The

tablets also contain inactive

ingredients: croscarmellose

sodium, hydroxypropyl

betadex, hydroxypropyl

cellulose, microcrystalline

cellulose and magnesium

stearate.

The tablet coating film

consists of FD&C Blue No.

1, FD&C Yellow No. 5,

ferric oxide yellow,

hypromellose 2910,

polydextrose, polyethylene

glycol 8000, titanium dioxide

and triacetin.

The Applicant accepted the

above suggestions.

For parenteral injectable

dosage forms, include the

name and quantities of all

inactive ingredients. For

ingredients added to adjust

the pH or make isotonic,

include the name and

statement of effect.

N/A

If alcohol is present, must

provide the amount of

alcohol in terms of percent

volume of absolute alcohol

N/A

Reference ID: 4715049

(b) (4)

OPQ-XOPQ-TEM-0001v06

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Effective Date: February 1, 2019

Statement of being sterile (if

applicable)

N/A

Pharmacological/

therapeutic

class

UKONIQ (umbralisib) is a

specific and orally

bioavailable inhibitor of

phosphoinositide 3 kinase

delta (PI3Kδ) and casein

kinase 1epsilon (CK1ε).

Adequate

Chemical name, structural

formula, molecular weight

The active

pharmaceutical ingredient

is umbralisib tosylate,

which is a white to light

brown powder with the

molecular formula

S and a

molecular weight of

743.75 g/mol. Umbralisib

tosylate is freely soluble

in dimethyl sulfoxide,

soluble in methanol, and

practically insoluble in

water.

The chemical name for

umbralisib tosylate is (S)-

2-(1-(4-amino-3-(3-fluoro-

4-isopropoxyphenyl)-1H-

pyrazolo [3, 4-d]

pyrimidin-1-yl)-ethyl)-6-

fluoro-3-(3-fluorophenyl)-

4H-chromen-4-one 4-

methylbenzenesulfonate

and has the following

structure:

Adequate

Reference ID: 4715049

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Effective Date: February 1, 2019

Section 11 (DESCRIPTION) Continued

Item

Information Provided

in the NDA

Assessor’s Comments

For oral prescription drug

products, include gluten

statement if applicable

N/A

Remove statements that

may be misleading or

promotional (e.g.,

“synthesized and developed

by Drug Company X,”

“structurally unique

molecular entity”

N/A

1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)

If radioactive, statement of

important nuclear

characteristics.

N/A

Other important chemical or

physical properties (such as

pKa or pH)

No other important physical

properties such as pKa or

pH are listed in the label.

Recommendation: Include

the pKa or pH value of the

drug substance in Section

11.

The Applicant included “The

ionization constant (pKa) of

umbralisib tosylate is 2.71.”

in response dated

December 12, 2020; the

response is acceptable.

Item

Information Provided

in the NDA

Assessor’s Comments

HOW SUPPLIED/STORAGE AND HANDLING section

Available dosage form(s)

Tablets

Adequate

Strength(s) in metric system

200 mg

Adequate

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v06

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Effective Date: February 1, 2019

Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) (Continued)

Item

Information Provided

in the NDA

Assessor’s Comments

Special handling about the

supplied product (e.g.,

protect from light,

refrigerate). If there is a

statement to “Dispense in

original container,” provide

reason why (e.g. to protect

from light or moisture, to

maintain stability, etc.)

N/A

If the product contains a

desiccant, ensure the size

and shape differ from the

dosage form and desiccant

has a warning such as “Do

not eat.”

No desiccant is used in

container closer system.

Storage conditions. Where

applicable, use USP

storage range rather than

storage at a single

temperature.

Store tablets at 68°F to

77°F (20°C to 25°C).

Excursions permitted

between 59°F and

86°F (15°C and 30°C)

[see USP Controlled

Adequate

Available units (e.g., bottles of

100 tablets)

Each bottle contains

120 tablets (30-day

supply).

Adequate

Identification of dosage forms,

e.g., shape, color, coating,

scoring, imprinting, NDC

number

Green, film-coated,

oval-shaped tablets

debossed with “L474”

on one side and plain

on the other

Adequate

Assess if the tablet is scored.

If product meets guidelines and

criteria for a scored tablet,

state “functionally scored”

N/A

For injectable drug products for

parental administration, use

appropriate package type term

(e.g., single-dose, multiple-

dose, single-patient-use).

Other package terms include

pharmacy bulk package and

imaging bulk package.

N/A

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v06

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Effective Date: February 1, 2019

Room Temperature].

Latex: If product does not

contain latex and

manufacturing of product

and container did not

include use of natural

rubber latex or synthetic

derivatives of natural rubber

latex, state: “Not made with

natural rubber latex. Avoid

statements such as “latex-

free.”

Drug product doesn’t contain

latex; no latex is used in drug

product container closer

system.

Include information about

child-resistant packaging

White opaque round

150cc high density

polyethylene (HDPE)

bottle capped with a 38

mm child resistant

polypropylene closure

with heat sealed

peelable foil liner.

Adequate

1.2.5 Other Sections of Labeling

Assessor’s comment: Regarding FD&C Yellow No. 5, refer to section 11.

1.2.6 Manufacturing Information After Section 17 (for drug products)

Item

Information Provided

in the NDA

Assessor’s Comments

Manufacturing Information After Section 17

Name and location of

business (street address,

city, state and zip code) of

the manufacturer, distributor,

and/or packer

Distributed and

Marketed by: TG

Therapeutics, Inc.

Edison, NJ 08837

There is no street address for

the company; a comment was

issued to the Applicant by

Labeling Division to request for

street address per 21 CFR

201.1 and 21 CFR 201.100(e).

In response dated December

07, 2020, the Applicant provided

street address, 343 Thornall

Street, Suite 740.

2.0 PATIENT LABELING

Reference ID: 4715049

(b) (4)

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Effective Date: February 1, 2019

Assessment of Product Quality Related Aspects of Patient Labeling (e.g.,

Medication Guide, Patient Information, Instructions for Use):

CMC related information in Patient Information is the same as in USPI. Refer to

the above evaluation for details.

3.0 CARTON AND CONTAINER LABELING

3.1 Container Label

3.2 Carton Labeling

Only the draft labeling for the bottle is provided. There is no carton mentioned in

container closure system. The following review is for the bottle labeling.

Item

Information Provided in the

NDA

Assessor’s

Comments about

Carton Labeling

Proprietary name,

established name, and

dosage form (font size and

prominence

UKONIQ

Adequate

Dosage strength

200 mg

Adequate

If the active ingredient is a

salt, include the

equivalency statement per

FDA Guidance

Each tablet contains 200 mg

umbralisib free base equivalent to

260.2 mg of umbralisib tosylate.

Adequate

Net contents (e.g. tablet

count)

120 Tablets

Adequate

Reference ID: 4715049

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Effective Date: February 1, 2019

“Rx only” displayed on the

principal display

Yes

Adequate

NDC number

NDC 73150-200-12

Adequate

Lot number and expiration

date

Yes, included.

Adequate

Storage conditions. If

applicable, include a space

on the carton labeling for

the user to write the new

BUD.

Store tablets at 68°F to 77°F

(20°C to 25°C). Excursions

permitted between 59°F and 86°F

(15°C and 30°C) [see USP

Controlled Room Temperature].

Keep out of reach of children.

Adequate

For injectable drug

products for parental

administration, use

appropriate package type

term (e.g., single-dose,

multiple-dose, single-

patient-use)

N/A

Other package terms

include pharmacy bulk

package and imaging bulk

package which require “Not

for direct infusion”

statement.

N/A

If alcohol is present, must

provide the amount of

alcohol in terms of percent

volume of absolute alcohol

N/A

Bar code

Yes

Adequate

Reference ID: 4715049

OPQ-XOPQ-TEM-0001v06

Page 11

Effective Date: February 1, 2019

Item

Information Provided in the

NDA

Assessor’s

Comments about

Carton Labeling

Name of

manufacturer/distributor

TG Therapeutics, Inc.

Adequate

Medication Guide (if

applicable)

N/A

No text on Ferrule and Cap

overseal

N/A

When a drug product differs

from the relevant USP

standard of strength,

quality, or purity, as

determined by the

application of the tests,

procedures, and

acceptance criteria set forth

in the relevant

compendium, its difference

shall be plainly stated on its

label.

N/A

And others, if space is

available

Assessment of Carton and Container Labeling: Adequate

ITEMS FOR ADDITIONAL ASSESSMENT

None

Overall Assessment and Recommendation:

The Applicant has made all the updates as requested. The labeling is adequate from

CMC perspective.

Primary Labeling Assessor Name and Date: Yang Nan, Ph.D.

Secondary Assessor Name and Date (and Secondary Summary, as needed):

Anamitro Banerjee, Ph.D., Branch Chief

Reference ID: 4715049

Yang

Nan

Digitally signed by Yang Nan

Date: 12/07/2020 04:23:30PM

GUID: 520bd6c90002b3b0320380334e69a817

Anamitro

Banerjee

Digitally signed by Anamitro Banerjee

Date: 12/07/2020 04:44:47PM

GUID: 5075764700003844b7bc89632228509f

Reference ID: 4715049

23 Pages have been Withheld in Full as B4 (CCI/TS)

Immediately Following this Page

CHAPTER VI: BIOPHARMACEUTICS

NDA Number

213176; 505 b (1)-NME

Assessment Cycle Number

Drug Product Name/

Strength

UKONIQ™ (umbralisib) Tablets

200 mg

Route of Administration

Oral (800 mg orally once daily with food)

Applicant Name

TG Therapeutics, Inc.

Therapeutic Classification/

OND Division

Oncology

OND/DHM2

Associated INDs

IND 116762 (Phase 1 study TGR-1202-101)

IND (pivotal Phase 2b study UTX-TGR-205)

Proposed Indication

UKONIQ is a kinase inhibitor indicated for the treatment

of adult patients with:

• Marginal zone lymphoma (MZL) who have received at

least one prior anti-CD20-based regimen.

• Follicular lymphoma (FL) who have received at least

prior systemic therapies.

Accelerated approval was granted for MZL and FL based

on overall response rate. Continued approval for these

indications may be contingent upon verification and

description of clinical benefit in a confirmatory trial.

Primary Reviewer

Qi Zhang, Ph.D.

Secondary Reviewer

Om Anand, Ph.D.

Assessment

Recommendation

Adequate

Assessment Summary:

The Applicant, TG Therapeutics, is seeking approval of the proposed UKONIQ™

(umbralisib) Tablets, 200 mg for the treatment of adult patients with marginal zone

lymphoma (MZL) and follicular lymphoma (FL). Umbralisib is a novel inhibitor of

phosphoinositide 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε). The proposed

Umbralisib Tablet is an immediate release, green film coated tablet containing 200 mg

umbralisib (free base). The clinical program in support of this NDA includes an ongoing

pivotal Phase 2b study (UTX-TGR-205), an ongoing Phase 2 study (TGR-1202-202), and

a first-in-human, dose escalation, Phase 1 study (TGR-1202-101).

The Biopharmaceutics review is focused on evaluation of (i) the adequacy of the proposed

dissolution method and acceptance criterion, (ii) bridging throughout the drug product

development, and (iii) risk assessment.

1) Dissolution Method and Acceptance Criterion

200 mg of umbralisib free base equivalent to 260.2 mg of umbralisib tosylate

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Per agreement under IND meeting dated August 13, 2018, the dissolution method

was redeveloped

. Based on the totality of the information and data provided [complete

dissolution at 45 minutes, method’s discriminating ability against critical process

parameters, and relevant Biopharmaceutics considerations (control of API particle size,

and Tmax is not critical], the dissolution method proposed by the Applicant in the current

submission, using 0.05 M phosphate buffer pH 6.8 with 0.5% sodium lauryl sulphate and

acceptance criterion of Q = % at 45 minutes, for the drug product batch release and

stability testing are acceptable.

Approved Dissolution Method and Acceptance Criterion for

UKONIQ™ (umbralisib) Tablets, 200 mg

Apparatus

Speed

Medium

Volume/Temp

Acceptance

Criterion

USP Apparatus

1 (Basket, 10

mesh)

100 rpm

0.05 M phosphate buffer

pH 6.8 with 0.5%

sodium lauryl sulphate

900 mL/37℃

Q % in 45

minutes

2) Bridging Throughout Product Development

The proposed to-be-marketed Umbralisib Tablets, film coated, 200 mg have the same

formulation and manufacturing site as the batches used in the pivotal clinical study [Phase

2b Study UTX-TGR-205]. Thus, bridging between the clinical formulation and

commercial product is not needed.

3) Biopharmaceutics Risk Assessment

The initial risk deemed dissolution as “Moderate” from a Biopharmaceutics standpoint,

because the drug substance has low solubility. The Applicant has included drug substance

particle size acceptance criterion. Additionally, the Tmax (4 hours) of Umbralisib is not

considered critical regarding treatment effect or disease control for the proposed

indication. The risk can be further mitigated with the implementation of the dissolution

specification for the proposed drug product.

List Submissions Being Assessed:

Document(s) Assessed

Date Received

Original Submission

01/10/2020

Response to Information Request

07/21/2020

Concise Description of Outstanding Issues (List bullet points with key information

and update as needed):

None.

Recommendation:

From a Biopharmaceutics perspective, NDA 213176 for UKONIQ™ (umbralisib) Tablets,

200 mg is recommended for APPROVAL.

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B.1 BCS DESIGNATION

Assessment: A BCS designation is not requested nor required.

The Applicant claimed that umbralisib tosylate is a BCS Class 2 drug with low solubility

and high permeability because umbralisib tosylate exhibits low solubility (over pH range

of 1 to 7.4) and high permeability based on a MDCK-MDR1 cell assay.

Solubility: Umbralisib tosylate was identified as a single crystal form (Form 1) and it has

been used in clinical supplies and registration stability batches. The Applicant submitted

the solubility data (Table 1) for umbralisib tosylate at different pH values and varying

surfactant concentrations.

Table 1: Solubility of Umbralisib Tosylate in Different Media

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The solubility data are consistent with the indicated BCS class of the drug substance, as

the solubility is 0.16 mg/mL in 0.1 N HCl, < 0.01 mg/mL at higher pHs, and 0.015 mg/mL

in water, whereas the minimum required solubility is 3.2 mg/mL in 250 mL for the single

800 mg-dose. The solubility increases in the presence of surfactants, e.g., 1.93 mg/mL in

0.05 M phosphate buffer with 0.5% SLS, in the proposed dissolution medium.

Permeability: The apparent permeability (Papp) values were measured with the

absorptive (apical to basolateral) permeability of 2.22, 9.30, and 3.53 × 10

-6

cm/sec and

secretory (basolateral to apical) permeability of 2.14, 6.85, and 1.09 × 10

-6

cm/sec, using

1 µM, 10 µM, and 100 µM umbralisib tosylate, respectively.

Note that the absolute bioavailability and relative bioavailability of umbralisib have not

been determined. According to the labeling, approximately 81% of the dose was

recovered in feces (17% unchanged) and 3% in urine (0.02% unchanged) following a

single radiolabeled dose of umbralisib 800 mg to healthy subjects.

B.2 DISSOLUTION METHOD AND ACCEPTANCE CRITERION

Assessment: Adequate

Drug Product: The proposed 200 mg Umbralisib Tablets are green film-coated, oval

shaped, debossed tablets containing active ingredient umbralisib tosylate 260.2 mg,

microcrystalline cellulose and croscarmellose ,

hydroxypropyl cellulose , magnesium stearate . The drug product is

manufactured by

. The drug product is dissolving in 45 minutes using the proposed

dissolution method.

Dissolution Method Development:

Reference ID: 4715049

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Validation of Dissolution Method: The final dissolution method proposed has been

validated with respect to the analytical HPLC method (refer to the Drug Product Review),

and the complete dissolution data generated using the proposed dissolution method from

the clinical and registration/stability batches demonstrate the repeatability,

reproducibility, and robustness of the dissolution of the proposed drug product on a batch-

to-batch basis.

Dissolution Acceptance Criterion: The dissolution acceptance criterion of Q= % at

45 minutes is proposed by the Applicant based on the dissolution profiles from 1)

investigation of the selection of the dissolution medium and the method’s discriminating

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ability, and 2) batch release data for most recent three clinical batches (Figure 9; Table

2) and long term stability data up to 18 months for the registration/stability batches (6 M,

9 M, and/or 12 M and 18 M) (Table 3).

Figure 9: Dissolution Profiles of 3 Recent Clinical Batches at Release

Table 2: Summary of Mean Dissolution Data at Release

for 3 Recent Clinical Batches

Time (minutes)

Minimum Mean % Dissolution

Maximum Mean % Dissolution

Table 3: Summary of Mean Dissolution for Registration Batches

after Storage for up to 18 Months

Time (minutes)

Minimum Mean % Dissolution

Maximum Mean % Dissolution

As recommended by the FDA under IND 116762 CMC Type B Meeting 08/13/2018, to

bridge the old and new (pH 6.8/0.5% SLS)

dissolution methods for stability, dissolution profiles in the 3 media were collected for all

the registration batches for new stability time points and will continue to be collected in

the 3 media for the rest of the stability program. Note that dissolution of the registration

stability batches at all time points in the new medium (pH 6.8/0.5% SLS) meet the

proposed specifications of Q= % at 45 minutes, and no significant change in dissolution

for long-term stability data up to 18 months tested.

Reference ID: 4715049

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B.3 CLINICAL RELEVANCE OF DISSOLUTION METHOD & ACCEPTANCE

CRITERIA (e.g., IVIVR, IVIVC, In Silico Modeling, small scale in vivo)

Assessment: N/A

Data Evaluating the PK of Different Formulation Variants: Two formulations

containing different particle size drug substance lots were evaluated in the BA PK study

(TGR-1202-PK102). One batch (batch #1305005591) was manufactured using

The other batch (batch # S0113035)

was manufactured using . PK results of these

two batches are provided in Table 4. The systemic exposure (AUC) after administration

of the drug product containing umbralisib drug substance was 60% higher

than that after administration of the drug product containing umbralisib

drug substance. In addition, dissolution profiles of tablets made with drug

substance was shown significantly higher than that of

drug substance in an acidic dissolution medium (0.1 N HCl

with 1% SLS) as tested (Figure 10). Therefore, the decision was made to

drug substance for further formulation development and clinical batches manufacture,

and a three-tier particle size control

has been included in the drug substance specification.

Table 4: Human Pharmacokinetic Results for Evaluation of Drug Substance

Particle Size in 200 mg Umbralisib Tablets

Pharmacokinetic

Parameter

Tablet batch 1305005591

Tablet Batch S0113035

AUC

(ng*hr/mL)

5914 (33.6)

9440 (26.9)

AUC

∞

(ng*hr/mL)

7940 (37.7)

12324 (29.8)

max

(ng/mL)

167 (41.7)

372 (35.1)

max

(hr)

3.00 (2.00, 6.00)

3.00 (2.00, 4.03)

Figure 10: Dissolution Profiles of Tablets with

and Drug Substance in 0.1 N HCl with 1% SLS

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B.12 BRIDGING OF FORMULATIONS

Assessment: Adequate

The following changes were made to the 200 mg umbralisib film-coated tablets

throughout product development:

. A list of all the batches manufactured

for clinical trials is presented in Table 35 Section 3.2.P.22. The table outlines the changes

that were made throughout the development of this product as described above and a

comparison between early clinical, pivotal clinical and the commercial (to be marketed)

formulation. The specific clinical trials that these batches were used for are summarized

in Table 11 Section 2.7.1. The formulation composition of the commercial batches is the

same as the most recent 13 clinical batches used in most of the clinical trials. Among the

13 clinical batches, three were registration batches (1705004779, 1705007655 and

1805003844). Therefore, no additional information is needed to bridge the drug product

formulations.

Reference ID: 4715049

(b) (4)

Zhang

Digitally signed by Qi Zhang

Date: 11/03/2020 12:07:10PM

GUID: 547e178000007695c91eb10380b07939

Anand

Digitally signed by Om Anand

Date: 11/03/2020 03:28:59PM

GUID: 508da6fb0002833385a1485d53137893

Reference ID: 4715049

--------------------------------------------------------------------------------------------

This is a representation of an electronic record that was signed

electronically. Following this are manifestations of any and all

electronic signatures for this electronic record.

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/s/

------------------------------------------------------------

SHERITA D MCLAMORE

12/10/2020 01:32:38 PM

Signature Page 1 of 1

Reference ID: 4715049