# Presentation: 321574

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**
**René Rizzoli M.D.**
**Division of Bone Diseases**
**[WHO Collaborating Center **
**for Osteoporosis and Bone Diseases]**
**Geneva University Hospital**
**Geneva, Switzerland**

## Preclinical Studies

| Guidelines | Main objectives (1) |
| --- | --- |
| FDA 1994 | Opportunity to directly examine 
bone mass, architecture and strength |
| WHO 1998 |  To establish the relationship between the effects of an intervention 
on bone mass and bone strength  |
| CPMP 2001 | Documentation of drug-induced effects on bone architecture and strength |

**Preclinical**** ****Studies**

## Preclinical Studies

| Guidelines | Main objectives (2) |
| --- | --- |
| FDA 1994 | To demonstrate that long term treatment will not lead 
to deleterious effects on bone quality |
| WHO 1998 | To establish the effects of long term exposure on the quality of skeletal tissue 
 |
| CPMP 2001 | Important component of the initial efficacy and safety assessment |

**Preclinical**** ****Studies**

## Preclinical Studies

| Guidelines | Main objectives (3) |
| --- | --- |
| FDA 1994 |  |
| WHO 1998 | To elucidate the mechanism of action of
a pharmaceutical agent and thus provide the rationale for its use in humans
______
To examine the effects of an intervention
on fracture repair |
| CPMP 2001 |  |

**Preclinical**** ****Studies**

## Preclinical Studies: Specific Issues

**Species**
**Study Design**
**	****Reflective of Clinical Situation **(Prevention/Treatment)
**	****Treatment Schedule **(Continuous/Intermittent)
**	****Doses**
**	****Duration**
**	****Variables **
**	**(Mass, Density, Architecture, Histology, Biomechanics, Remodeling)
**	**

## Predictive values of preclinical studies

**As far as the animal model chosen **
**pertaines to the clinical situation **
**for which the drug is evaluated, **
**the results of preclinical studies **
**(relation BMD-strength; **
**bony tissue tolerance) **
**are ****highly predictive**** of clinical outcome **
**for most, if not all, drugs tested **

## Alendronate Reduces the Risk of Morphometric Vertebral Fractures

**0**

**2**

**4**

**6**

**Without VFx**

**With VFx**

**Incidence (%) per year r**

**Placebo**

**Alendronate**

**Reduction = 44%**
**  ****p = 0.001**

**Reduction **
**= 47%**
**  ****p < 0.001**

_**Vertebral Fracture Status at Baseline**_

- Cummings SR, et al. *JAMA.* 1998; 280:2077-2082.

- Black DM, et al. *Lancet.* 1996; 348:1535-1541.

**BMD**

**Bone Strength**

**Alendronate Increases**
**BMD and Bone Strength**
**in Baboon Vertebrae**

- Balena et al., JCI 92:2577-86,1993

## Risedronate Increases Vertebral Bone Strength 

**1200**

**1300**

**1400**

**1500**

**1600**

**1700**

**1800**

**1900**

**2000**

**Control**

**2.5mg/kg/d**

**MPa**

*****

- Dufresne, et al, JBMR 2001; 16 (Suppl 1):  S404.

**Minipig Vertebrae**

**Effect of Risedronate on**
**Radiographic Vertebral Fractures**

**Years 0-3**

**PBO**

**RIS**

**PBO**

**RIS**

**41%**
**Reduction**
***P *****< 0.003**

**49%**
**Reduction**
***P *****< 0.001**

**% of Patients with Fracture**

- 1Harris et al. *JAMA*. 1999;282:1344–1352.
- 2Reginster JY. *Osteoporos Int*. 2000;11:83–91.

## Raloxifene Preserves 

**Raloxifene Preserves **
**Bone Strength ****in the Ovariectomized Rat**

**Breaking Force (N)**

**250**

**275**

**300**

**325**

**350**

**375**

**400**

*****

*****

**Sham     OVX ****	****RLX**

**Vertebrae**

**Effect of Raloxifene Treatment **
**In Women **
**With or Without **
**Existing Fractures**

**0**

**5**

**10**

**15**

**20**

**25**

**Placebo**

**RLX 60**

**No Existing **
**Fractures**

**Existing **
**Fractures**

**% Patients with Incident Fracture**

**RR 0.5**
**(0.3, 0.7)**

**RR 0.7**
**(0.6, 0.9)**

*****

*****

**Ettinger et al. 1999**

**Vertebral Deformity**

## rhPTH(1-34) Increases Strength of Monkey Vertebrae

**Yield Force (N)**

- *

- Sato et al.  Osteoporos Int  2001

**Sham**

**OVX**

**PTH1**

**PTH5**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**Placebo**

**PTH 20**

**PTH 40**

**Patients (%) with ******** 1 Fracture**

***P<0.001**

**rhPTH(1-34) Reduces the Risk of New Vertebral Fractures**

**RR 0.35 (95% CI, 0.22, 0.55)***

**RR 0.31 (95% CI, 0.19, 0.50)***

- Neer et al.  NEJM  2001

## *

**Compression Test **
**of Vertebra (L4)**

**0**

**100**

**200**

**300**

**400**

**0**

**225**

**450**

**900**

*****

**Ultimate Strength (N)**

**Mean**** ± SEM. * p<0.05 vs control group**

**CUMULATIVE INCIDENCE OF PATIENTS **
**WITH NEW VERTEBRAL FRACTURE**

******* P < 0.001**

**Placebo**

**SR**

**35**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**0**

** ****1****st**

**2****nd**

**3****rd**

**Year**

*****

*****

*****

**% patients**

**Relative Risk of vertebral fracture: - 41%**

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Failure to Evaluate Bone Strength in**
**Preclinical Efficacy Assessment**
**Ex. Fluoride Salts**
**Major Increase in BMD of the Axial Skeleton, but ****No**
**	****Reduction**** in Vertebral Fracture Risk**
- (Hagenhauer et al, 2001)
**No**** Significant ****Improvement**** of Bone Strength**
**	****in Various Animal Models**
- (Sogaard et al, 1995, Lafage et al, 1995, Turner et al, 1996)

## Slide 13

|  | Animal studies |  | Clinical Trials |  |
| --- | --- | --- | --- | --- |
|  | BMD | Bone Strength | BMD | Reduced
Fracture Rate |
| Etidronate | + + |  ? (Mineralization
Defect) | + | Not 
observed |
| Alendronate | + + | + + | + + | + + |
| Risedronate | + + | + + | + + | + + |
| Raloxifene

Fluoride | + +

+ | + +

Not improved | +

+ + + + | + +

Not 
observed |
| hPTH 1-34 | + + | + + + | + + + | + + |
| Strontium
Ranelate  | +  | + + | + ++  |  + + |

## Preclinical Studies

| Guidelines | Impact on clinical study timing  |
| --- | --- |
| 
FDA 1994 | Submission of final reports 
from studies in rats and non rodents after phase III, 
between Pre-NDA meeting and submission of NDA |
| WHO 1998 | Well documented preclinical evaluation generally
appropriate before phase III. 
Evaluation before start of clinical program 
should include pharmacodynamic and bone tolerance data     |
| CPMP 2001 | Studies in OVX rats and in the second animal model should be timed so as to provide guidance for phase II and support for phase III, resp.
 |

**Preclinical Studies**

## Preclinical Studies

| Guidelines | Impact on clinical study program  |
| --- | --- |
| 
FDA 1994 | 
Bone quality “normal” or “abnormal“ determines :
- Drug approval for marketing
- Duration of controlled studies (phase III)
- Duration of phase IV open studies
 |
| 
WHO 1998 | Bone quality “normal” or “uncertain”, 
and mechanism of action well- or ill-understood determine:
- End points (biomark. or BMD) for dose selection in phase II
- Entering phase II
- BMD or Fx may be appropriate end-point in phase III |
| 
CPMP 2001 | 

No impact
 |

**Preclinical Studies**

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Issues to be Clarified**
**Relation Bone Mass - Bone Strength **
**	****(How to Detect an Exeption)**

## BMD, Cancellous Bone Volume and Bone Formation Rate

**BMD (mg/cm2)**

*****

**°**

**°**

**0**

**5**

**10**

**15**

**20**

**25**

*****

*****

*****

**Proximal tibia**
**BV/TV (%)**

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

*****

***° ¥**

**BFR/BS (μm3/μm2/d)**

**BMD, Cancellous Bone Volume and Bone Formation Rate**
**in Adult Female Rats Treated with the SERM MDL103,323 **
**or the Bisphosphonate Pamidronate at Doses **
**Similarly Increasing Bone Strength**
**(Bourrin et al., Bone 2002)**

**SHAM OVX OVX OVX **
**                 ****+ MDL+ Pam**

**SHAM OVX OVX OVX **
**                 ****+ MDL+ Pam**

**SHAM OVX OVX OVX **
**                 ****+ MDL+ Pam**

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Issues to be Considered**
**Relation Bone Mass - Bone Strength **
**	****(How to Detect an Exeption)**
**2. ****	****Heterogeneity of Action within a Drug Category**

## *

**0**

**50**

**100**

**150**

**200**

**250**

**Vertebral Strength**

**SHAM     OVX      OVX     OVX**
**	****          ****HMR****	****     RAL**
**	****          ****0.3         3.0**
**	****           ****mg/kg BW**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**700**

**800**

**900**

**SHAM     OVX      OVX     OVX**
**	****          ****HMR****	****     RAL**
**	****          ****0.3         3.0**
**	****           ****mg/kg BW**

** ****Serum IGF-I**

*****

*****

**The Decrease in Bone Mass and Bone Strength**
**Induced by Ovariectomy is corrected **
**by the SERM HMR 3339**

- Ammann et al, ASBMR 2002

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Issues to be Considered**
**Relation Bone Mass - Bone Strength **
**	****(How to Detect an Exeption)**
**Heterogeneity within a Drug Category**
**Safety Window (Anabolic Agents: Dose x 5)**

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Issues to be Considered**
**Relation Bone Mass - Bone Strength **
**	****(How to Detect an Exeption)**
**Heterogeneity within a Drug Category**
**Safety Window (Anabolic Agents: Dose x 5)**
**Integration of Preclinical Studies in **
**	****the Drug Development Strategy**
**	****(Complementarity, Definition of Study Design Including End-Points, Population)**

## Strategies for drug development in osteoporosis according to the 1998 WHO guidelines

**Preclinical****	****	****	****Phase II****	****	****	****	****Phase III**
**Quality of bone normal****	****	****Validated biochemical indices****	****	****BMD may be an ****	****	****	****	**** of turnover appropriate for dose ****	****appropriate**
**Mechanism of action ****	****	****selection****	****	****	****	****end-point**
**Understood****	****	****	**
**Quality of bone normal****	****	****Bone mineral measurements****	****	****Fracture may be a**
**	****	****	****	****to assess dose****	****	****	****	****necessary end-****	**** Mechanism of action ****	****	****	****	****	****	****	****point**
**ill-understood****	****	****	****	****	****	**
**Quality of bone uncertain****	****BMD and other end-points****	****	****Fracture is an ****	****	****	****	****	****appropriate****	****	****	****	****appropriate****	**** Mechanism of action ****	****	****	****	****	****	****	****end-point**
**understood**
**Quality of bone ****	****	****Unlikely to enter phase II**
**abnormal or uncertain****	**
**Mechanism of action**
**ill-understood**

## Preclinical Models of Drug Efficacy 

**and Skeletal Toxicity**

**Focus on Bone Strength Measured **
**at Various Skeletal Sites**
**Looking at Consistency in the Relation with**
**Bone Mass/Density**
**Geometry**
**Microarchitecture**
**Remodeling**
**Histology**

## Slide 24

## Preclinical Studies

| Guidelines | Animal Models: Study Design |
| --- | --- |
| FDA 1994 | 
Reflective of clinical indication
- Preventive
- Curative
Treatment schedule (continuous vs intermittent) should be the
same as that intended for clinical use
 |
| WHO 1998 | Idem FDA 1994
It should establish a rationale for the type of treatment schedule used later in humans |
| CPMP 2001 | Idem FDA 1994 |

**Preclinical**** ****Studies**

## Preclinical Studies

| Guidelines | Animal Models: Study Design. Duration |
| --- | --- |
| 
FDA 1994 | 
Based on bone turnover: 
Primates: 16 months
Rats: 12 months |
| 
WHO 1998 | 
Based on phase III duration
Large animal: 1/2 time selected for phase III evaluation
Rats: 1/4 time selected for phase III evaluation  |
| 
CPMP 2001 | 
Based on bone turnover:
Rat and large animals: at least 6 remodeling cycles

 |

**Preclinical**** ****Studies**

## Preclinical Studies

| Guidelines | Animal studies |
| --- | --- |
| 
FDA 1994 | 
Bone mass/density measurement
Analysis of bone architecture /histology
Biomechanical testing of bone strength
Biochemical markers of bone turnover
 |
| 
WHO 1998 | 
Similar recommendations but more detailed than FDA 1994
+ Fracture healing evaluation  |
| 
CPMP 2001 | 
Similar recommendations but less detailed than FDA 
1994 |

**Preclinical**** ****Studies**

## Data on Fracture Risk might not be Required

**Before First Registration**
**For a ****New Agent**** Provided:**
**Antifracture Efficacy has been Demonstrated with an Agent **
**	****of the Same Category**
**Similar Changes in BMD and Bone Turnover in Patients **
**	****Compared to this Agent**
**Similar Changes in Bone Strength in Animal Models**
**Similar Profile of Bone Safety**
**Combined Therapy**** **
**	****(2 Antiresorptives, 1 Anabolic + 1 Antiresorptive) **
**	****Provided:**
**Antifracture Efficacy Demonstrated for both Agents**
**Higher Bone Strength with the Combined Therapy than with one Agent Alone**
**-****	****Similar Profile of Bone Safety****	**

## Predictive values of preclinical studies

**The results of animals studies were able**
**to predict whether changes in bone mass**
**and/or bone mineral density **
**will be associated with modifications **
**in bone fragility and therefore **
**in fracture rate in osteoporotic patients**

## Preclinical Studies

| Guidelines | Animal Models: Species |
| --- | --- |
| FDA 1994 | 
Two species are required:
Adult ovariectomized rats 
2.  Larger remodeling species |
| WHO 1998 | Idem FDA 1994
+ other rodent and non rodents models according to the type of osteoporosis |
| CPMP 2001 | 
Idem FDA 1994
 |

**Preclinical**** ****Studies**