# Presentation: 508227

## NDA 22-291 PROMACTA® (Eltrombopag)

- FDA Review
- Andrew Dmytrijuk, MD

## Proposed Indication

-   **	****Eltrombopag is indicated for the short-term treatment of previously-treated patients with chronic idiopathic thrombocytopenic purpura (ITP) to **_**increase platelet counts**_** **_**and**_** **_**reduce or prevent bleeding**_**.**

**Underlines added for emphasis**

## Eltrombopag Background

** ****Tablet, administered daily**
** ****Binds to transmembrane portion of TPO ****	****receptor**
** ****Preclinical testing of Eltrombopag:**
** ****stimulated platelets only in chimpanzees**
** ****in other animals (in high doses):**
** ****Chronic progressive nephropathy**
** ****Liver abnormalities**
** ****Cataracts**
** ****Preclinical testing of another TPO ****	****receptor agonist: marrow fibrosis**

## Clinical Database Eltrombopag (E) exposure n = 1088

**Chronic ITP:**
**n = 330**
**Thrombocytopenia in hepatitis C: **
**n = 56  **
**Chemotherapy-induced thrombocytopenia:**
**n = 134 **
**Clinical pharmacology:**
**N = 568**

## ITP Program

**“****Short term”: 6 week exposure**
**- Completed: placebo controlled**
**	****	****- 773A**
**	****	****- 773B**
**- On-going, single arm: “REPEAT”****	**
**“****Long term”: ****≥**** 6 month exposure**
**- On-going: placebo controlled: “RAISE” **
**- On-going: single arm: “EXTEND” **

## Major Review Topics: “Short Term”

**Efficacy:**
**increase platelet counts**
**reduce or prevent bleeding**
**Safety:**
**bleeding risks following drug discontinuation**
**hepatotoxicity **
**“****short term” indication but long term usage**
**	****- more hepatotoxicity?**
**	****- potential marrow fibrosis?**

## Data Presentation

**Completed studies (short-term):**
**773A**
**773B**
**On-going studies/interim:**
**REPEAT (cycles of short-term)**
**EXTEND**
**RAISE**

## “Short Term” Rationale: Protocols

**	****“****Short term treatment may increase platelet counts in patients with chronic ITP **_**scheduled for surgical or dental procedures**_**, where a low platelet count can be a hindrance or even prohibitive of the procedure due to the risk of excessive bleeding.”**

**Underlines added for emphasis**

## Studies 773A and 773B: Design Features

**DB, PC, multi-national**
**Eligibility: **
**- platelets < 30K despite at least 1 prior therapy**
**- **_**did not**_** select patients scheduled for procedures**
**Randomization:**
**- 773A: placebo or active drug at                      ****	****	****	****30 mg, 50 mg or 75 mg daily**
**- 773B: placebo or active drug at 50 mg daily**

## 773A and 773B: Design Features, continued

**Dose adjustment:**
**- dosing terminated for Plt ct > 200K**
**- 773B: could increase dose to 75 mg at day 22**
**Major baseline and follow-up evaluations:**** **
**- CBC, clinical chemistry**
**- WHO bleeding score**
**Endpoints:**
**- Primary: Plt ct ****≥ 50K at day 43 or drug d/c ****	****	****	****	****due to Plt ct > 200K (“response”)**
**- Other: change in WHO bleeding score**

## 773A and 773B Baseline Characteristics

| Characteristic | Pooled 773A & 773B |  |
| --- | --- | --- |
|  | Placebo
n = 67 | 50 mg E 
n = 106 |
| Age, median | 46 yrs | 47 yrs |
| Female | 64% | 60% |
| Splenectomy | 42% | 43% |
| ≥ 2 prior tx | 70% | 75% |
| Plt ct, median | 17 K | 18 K |

**All randomized subjects**

## 773A and 773B Disposition

| feature | Pooled 773A & 773B |  |
| --- | --- | --- |
|  | Placebo
n = 67 | 50 mg E 
n = 106 |
| Completed 6 weeks “on therapy” | 78% | 65% |
| Discontinued drug | 22% | 35% |
|   - Plt ct > 200 K | 3% | 27% |
|   - Adverse event | 7% | 5% |
|   - Other | 12% | 3% |

## 773A and 773B  Primary Endpoint Results, n (%)

***P < 0.01 for Eltrombopag 50 mg versus placebo**

| study | Placebo
 | Eltrombopag 
50 mg  |
| --- | --- | --- |
| 773A “Responders” | 3/27 (11%) | 19/27
(70%)* |
| 773B “Responders” | 6/38 (16%) | 43/74 (58%)* |

## Primary Endpoint in Splenectomy Subsets, n (%)

| subset | Pooled 773A & 773B |  |
| --- | --- | --- |
|  | Placebo | 50 mg E  |
| Splenectomy | 4/27 (15%) | 26/44 (59%) |
| No splenectomy | 5/37 (14%) | 36/56 (64%) |

## 773A and 773B  Maximum Platelet Responses

| Platelet count | Placebo
n = 65 | Eltrombopag 50 mg
n = 101 |
| --- | --- | --- |
| > 200 K | 2 (3%) | 29 (29%) |
| > 400 K | 1 (2%) | 9 (9%) |
| > 600 K | 0 | 3 (3%) |

## WHO Bleeding Scores 

**Focused upon change from **_**baseline**_** bleeding ****	****	****score**
**Unclear clinical meaningfulness of changes in ****	****	****score (e.g., 2 to 1)**
***“******A method for objective quantification of bleeding symptoms in ITP has not been established.”***
**	****	****	****	****	****	****Br J Haematol 2007;138(2)245-8**
**Investigators: **
**subjectively assigned WHO score**
**aware of platelet counts**

## WHO Bleeding Scale 

**WHO Bleeding Scale**

| Grade | Descriptor |
| --- | --- |
| 0 | No bleeding |
| 1 | Petechiae |
| 2 | Mild blood loss |
| 3 | Gross blood loss |
| 4 | Debilitating blood loss |

## WHO Bleeding Scores in 773A and 773BDistribution of Change from Baseline Score to  “No Bleeding” Score at End of Therapy

| Group | n, % Subjects by Baseline Score |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | 0 | 1 | 2 | 3 | 4 |
| Eltrombopag | 35/39
90% | 26/44
59% | 4/17
24% | 2/2
 | - |
| Placebo | 20/26
77% | 9/26
35% | 3/9
33% | 1/3
 | - |

**Pooled placebo and 50 mg Eltrombopag groups**

## “Hemostatic Challenges” in 773A and 773B

| Group | Event | Plts | Rescue
Med | Blood 
trans |
| --- | --- | --- | --- | --- |
| Eltrom-bopag | Gall Bl surg | 428 | No | No |
|  | Gall bl surg | 369 | No | No |
|  | Dental | 80 | No | No |
|  | MVA | 491 | No | No |
| Placebo | Eye surg | 12 | IVIG | No |
|  | Hip surg | 25 | IVIG | Yes |
|  | Throat surg | 36 | Tx acid | No |

## Adverse Events: 773A and 773BPlacebo and 50 mg Eltrombopag cohorts

| Event | Placebo
n = 67 | Eltrombopag
n = 106 |
| --- | --- | --- |
| Any AE | 35 (52%) | 70 (66%) |
| Any SAE | 8 (12%) | 12 (11%) |
|    Hemorrhage | 1 (1%) | 6 (6%) |
|    Varicose V rupture* | 1 (1%) | 0 |
| Death | 0 | 1 (1%) |

***no ITP rescue medication reported**

## Death in Study 773A

- 66 year old man, hx pneumonectomy
- Day 15: increased ALT/AST
- Day 21: hospitalized for COPD exacerbation with 	liver and renal test abnormalities
- Died ~ day 26 of “cardiac failure caused by 	pulmonary failure”
- Autopsy: thromboemboli in lung and liver, R and L 	ventricular hypertrophy
- Eltrombopag-associated liver/renal test 	abnormalities?

## Subject 144 in Study 773A

- Liver/renal test abnormalities

| Lab | BsLn | Day 8 | Day 15 | Drug D/C |
| --- | --- | --- | --- | --- |
| ALT U/L
(ULN 45) | 21 | 15 | 274 | 1897 |
| AST U/L
(ULN 40) | 15 | 12 | 186 | 755 |
| Bili μm/L
(ULN 40) | 9 | 11 | 14 | 53 |
| Creat μm/L
(ULN 110) | 77 | 84 | 97 | 128 |
| BUN mm/L
(ULN 7) | - | - | - | 22 |
| Platelet, K | 5  | 10 | 44 | 108 |

## Major Safety Signals from 773A and 773B

**1.  Risk for liver toxicity**
**2.  Hemorrhage risk following ****	****Eltrombopag D/C**

## Risk for liver toxicity: 
 Eltrombopag undergoes liver metabolism
 Preclinical data show liver toxicity at 			high doses
 One death with liver test abnormalities 		and small imbalances in liver test 		abnormalities in general population

** ****Eltrombopag undergoes liver metabolism**
** ****Preclinical data show liver toxicity at ****	****	****	****high doses**
** ****One death with liver test abnormalities ****	****	****and small imbalances in liver test ****	****	****abnormalities in general population**

## Liver Tests, Max Toxicity Grade: 773A & 773B

| Outcome | Grade | Placebo
n = 67 | Eltrombopag 50 mg
n = 106 |
| --- | --- | --- | --- |
| ALT | 1 | 17 (26%) | 22 (21%) |
|  | 2 | 1 (2%) | 5 (5%) |
|  | 3 | 1 (2%) | 2 (2%) |
|  | 4 | 0 | 1 (1%) |
| AST | 1 | 12 (18%) | 27 (26%) |
|  | 2 | 0 | 1 (1%) |
|  | 3 | 1 (2%) | 2 (2%) |
|  | 4 | 0 | 0 |
| Total Bili | 1 | 5 (8%) | 15 (14%) |
|  | 2 | 2 (3%) | 3 (3%) |
|  | 3 | 1 (2%) | 1 (1%) |
|  | 4 | 0 | 0 |

## Hemorrhage risk following Eltrombopag D/C
 Compared to baseline, worsened 			thrombocytopenia following TPO-mimetic 	drug D/C
 Worsened thrombocytopenia, compared to 	baseline: 10% Eltrombopag vs 6% placebo
 Imbalance in serious hemorrhages following 	drug D/C

-  Compared to baseline, worsened 			thrombocytopenia following TPO-mimetic 	drug D/C
-  Worsened thrombocytopenia, compared to 	baseline: 10% Eltrombopag vs 6% placebo
-  Imbalance in serious hemorrhages following 	drug D/C

## Serious Hemorrhage Adverse Events: with use of rescue medications

| Group | Event | Period | Platelets |
| --- | --- | --- | --- |
| E | Rectal Hem | Off Tx ~ 9 d | < 50 K |
| E | Petechaiae | Off Tx ~ 21 d | < 10 K |
| E | Epistaxis | Off Tx ~ 32 d | < 10 K |
| E | Subarach H | Off Tx ~ 30 d | < 20 K |
| E | Menorrhag | Off Tx* ~ 14 d | < 10 K |
| E | Cereb Hem | On Tx ~ 11 d | < 10 K |
| E | GI Hem | On Tx ~ 15 d | < 20  K |
| Placebo | Cer & GI Hem | On Tx ~ 14 d | < 20 K |

*** 75 mg Eltrombopag**

## On-going: REPEAT

**Design:**
**eligible: platelets ****≥ 20K and ≤ 50K & 1 prior tx**
**3 cycles of 6 weeks separated by up to 30 days “off therapy”**
**Primary endpoint: proportion of subjects with platelet response****, given a response in cycle 1**
**Limitations: **
**“****off therapy” period can be shortened**
**Uncontrolled, interim data**

## REPEAT:

**Platelet Response**

| Time | Responders |
| --- | --- |
| Cycle 1 | 51/66 (77%) |
| Cycle 2 | 29/33 (88%) |
| Cycle 3 | 13/16 (81%) |

## REPEAT:

**Hemostatic challenges**

| Event | Plts | Rescue
Meds | Blood Tx |
| --- | --- | --- | --- |
| Sinus surgery | 83 | No | No |
| Cardiac catheterization | 178 | No | No |
| Colonoscopy | 101 | No | No |
| Dental | 150 | No | No |
| Prostate (TURP) | 126 | No | No |
| Colon polypectomy | 130 | No | No |
| Dental | 81 | No  | No |

## REPEAT: Major Safety Findings

-  **1 Serious hemorrhage: epistaxis and ear ****	****hemorrhage, off therapy**
** ****25/66 (38%) required Eltrombopag at a ****	****time point before 30 days “off therapy” due ****	****to platelets < 20K or bleeding symptoms **
** ****~ 15% rate of liver test abnormalities:            ****	****grade 1 or 2**** **

## On-going: EXTEND

**Design:**
**Eligible: completed prior study**
**Long term exposure with Eltrombopag dose adjustment and attempt to reduce/eliminate concomitant meds**
**Bone marrow reports after one year**
**Primary endpoint: safety**
**Limitations: uncontrolled, interim data**
**Platelet data n = 109**
**Overall safety n = 207**

## EXTEND:

**Exposure: median of 98 days**

| Duration | Safety Update, n = 207 |
| --- | --- |
| ≥ 6 months, n | 74 |
| ≥ 12 months, n | 25 |
| ≥ 15 months, n | 9 |
| ≥ 24 months, n | 0 |

## Safety Data: EXTEND

**Hemostatic challenges in 13 subjects:**
** ****Pre-procedure rescue medications in 2 subjects**
** ****No bleeding complications **

## Safety Data: EXTEND

** ****4 Deaths**
**	****- MVA**
**	****- GI hemorrhage ~ 55 days after last dose**
**	****- Bronchiectasis/possible sepsis/DVT**
**	****- Unwitnessed death/few details**
**20 subjects with SAE**
**	****- 3 PE **
**	****- 3 hemorrhage**
**	****- 2 increased liver tests **
**	****- isolated other events**
** ****~ 15% rate of liver test abnormalities:   ****	****mainly grade 1 or 2**

## Bone Marrow Data: EXTEND

** ****Other TPO-mimetic molecules cause ****	****marrow fibrosis in animals**
**No marrow SAE in short term Eltrombopag ****	****studies**
**All subjects in EXTEND to have marrow ****	****exam after one year Eltrombopag**
**Marrows examined by site ****	****pathologists/reports summarized**
**no central/adjudicated review**
**terms/definitions variable**

## Bone Marrow Data: EXTEND

** ****To date: 19 subjects with marrow reports**
**17 obtained ****≥ 10 months exposure (other ****	****after 2 and 8 months exposure)**
**7/19 had “reticulin” documented in report**
**1 had “reticulin and trichrome stains show moderate fibrosis, moderate increase in type 3 collagen (reticulin) and mild increase in type 1 collagen”**
**1 had “myelofibrosis grade 2/3”**

## On-going: RAISE

** ****R, DB, PC, six month exposure**
** ****Remains blinded, to date 197 enrolled **
** ****1 death to date (CNS hemorrhage/nonresponder)**
** ****26 subjects with SAE “on therapy”**
**5 hemorrhage **
**4 cataract **
**3 liver test abnormalities**
**2 thromboses **
**other isolated events**
** ****3 subjects with “post-therapy SAE”          ****	****(bronchitis, PE, CNS hemorrhage)**

## Summary: Efficacy

** ****Increased platelet counts in 60 – 70% subjects**
** ****Bleeding assessed with scores at each visit****	**** **
** ****Incremental changes of ? meaningfulness**
** ****Investigators unblinded to platelet counts**
** ****Change predominantly from score of 1 to 0**
**Hemostatic challenges reported in only 7 subjects**
**4 Eltrombopag group: no rescue medication **
**3 Placebo group: rescue medication **

## Summary: Safety

**Imbalance in serious hemorrhagic events ****	****requiring rescue ITP medications**
** ****7 Eltrombopag group vs 1 placebo group**
** ****Most serious hemorrhage followed ****	****	****	****	****Eltrombopag discontinuation: 5/7**
**Imbalance in liver test abnormalities**
**small imbalance in predominantly grade 1 and 2**
**one death in a patient with rising liver test ****	****	****	****abnormalities **

## Summary: Eltrombopag in long term evaluation program

**Interim data/studies on-going**
**Controlled data still blinded**
**Continued signals of predominantly grade 1 ****	****& 2 liver test abnormalities**
**Bone marrow effects signaled by reticulin ****	****presence in 7/19 biopsies**

## Major Discussion Considerations:

**Efficacy:**
**increase platelet counts**
**reduce or prevent bleeding**
**Safety:**
**bleeding risks following drug discontinuation**
**hepatotoxicity **
**“****short term” indication but long term usage**
**	****- more hepatotoxicity?**
**	****- potential marrow fibrosis?**

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