1.7 Benefit/Risk ConclusionsIn conclusion, omacetaxine offers an...

1.7 Benefit/Risk Conclusions

In conclusion, omacetaxine offers an important therapeutic option for the treatment of CML

patients who have the T315I mutation, a population that has a clear unmet medical need and

no proven treatment options. In study CML-202, CML-CP patients treated with omacetaxine

achieved durable hematologic and cytogenetic responses with a rapid onset, and in advanced

disease phase patients (CML-AP and CML-BP) achieved high rates of CHR. For two patients

who achieved MCyR, hematopoietic stem cell transplantation (HSCT) became a therapeutic

option. The main safety finding was myelosuppression, a recognized complication of CML

therapy and an anticipated adverse event in these heavily pre-treated patients. The

myelosuppression was predictable, generally tolerable, reversible, and managed by adjusting

the number of dosing days per cycle. Non-hematologic toxicities were generally mild to

moderate in severity and typically not dose limiting. Overall, omacetaxine demonstrated an

acceptable benefit-to-risk ratio in heavily pretreated patients who have a poor prognosis and

no proven treatment options.



12 BENEFIT/RISK EVALUATION

The Bcr-Abl T315I kinase domain mutation is the most common mutation identified in CML

patients who have failed TKI therapy. Patients with this mutation do not respond to therapy

with any of the currently available TKIs. The life expectancy of these patients is considerably

reduced compared to TKI responders and they therefore have an urgent unmet medical need

for a proven and effective therapy.



Treatment with subcutaneously administered omacetaxine is effective in heavily pre-treated

patients with CML who have the T315I mutation. Patients with this mutation who were in

CML-CP at the time of treatment achieved durable hematologic and cytogenetic responses.

In addition the median overall survival of these patients in study CML-202 exceeded that

reported in the literature37-39. Patients with advanced disease achieved high rates of CHR

which is considered a valuable endpoint that is predictive of clinical benefit3-5. Similar and

supportive efficacy results were also seen in study CML-203, which assessed the

effectiveness of omacetaxine in CML patients who had failed two or more TKIs.

Omacetaxine has a manageable safety profile comprised primarily of predictable and

reversible myelosuppression. Myelosuppression is a common effect of any anti-leukemic

agent and is more frequent in patients who have been pre-treated with multiple therapies.



Following treatment with omacetaxine, nadir values were typically reached within 2 to

3 weeks after the first dose of each cycle, and recovery of blood counts generally occurred

within 1 to 3 weeks of the nadir. In clinical practice, physicians are experienced in modifying

doses and duration of treatment according to blood levels of neutrophils and platelets.

Myelosuppression was expected in such a cohort and planned for in the trial designs. As a

result, adjustment of dosing days, rather than change in dosage, was utilized successfully

during the clinical studies to manage toxicities.



The most common non-hematologic toxicities (diarrhea, fatigue, pyrexia, nausea, and

asthenia) were generally mild to moderate in severity and typically not dose-limiting.

SC omacetaxine was safely administered by the patient at home without direct medical

supervision. Patient self administration versus administration by a health care professional

showed no discernable meaningful differences in tolerability, and injection complications

were limited to mild site reactions.



The clinical experience describes a favorable benefit/risk profile for omacetaxine in the

proposed indication. A REMS has been proposed to help ensure that the safe, effective, and

convenient self administration experience from the clinical trials is translated to the post

approval setting. Additional labeling recommendations call for routine monitoring of blood

counts to appropriately track clinical effects and for the management of dosing adjustments

to maintain the benefit/risk balance.



Given the favorable benefit/risk profile for omacetaxine in adult CML patients who have the

Bcr-Abl T315I mutation and have failed imatinib therapy, omacetaxine offers the only

therapeutic treatment alternative for a patient population with a poor prognosis and no proven

treatment options.





8.4 Efficacy Conclusions

The CML T315I patient has no effective treatment options and there is an immediate need

for a proven therapy. Left untreated, these patients will experience disease progression and

shortened life expectancy. Treatment of the CML T315I patients with omacetaxine has

proven effective. In study CML-202, CML-CP patients treated with omacetaxine achieved

durable hematologic and cytogenetic responses with a rapid onset, and advanced disease

phase patients (CML-AP and CML-BP) achieved high rates of CHR. Two of the three

patients who left the study to receive an allogeneic HSCT had achieved a MCyR during

omacetaxine therapy. Treatment with omacetaxine also induced major molecular responses

in patients who had achieved a CCyR. The overall survival data from study CML-202

exceeds that from the literature37. Response data from study CML-203 are similar to the

study CML-202 data and provide support for the efficacy claim of omacetaxine.





1.5 Clinical Efficacy

Major cytogenetic response is an accepted surrogate for prolonged survival and was used as

the basis of the approvals for imatinib, dasatinib, and nilotinib. For CML-AP and CML-BP,

hematologic responses are considered the primary endpoints that are predictive of clinical

benefit.