Drug

Name

Indication(s)

Pharmacologic Class/Unmet Medical Needs

Polivy (polatuzumab vedotin-piiq)

Poligy is indicated in combination with bendamustine and a rituximab product for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least two prior therapies

Polivy is a CD79b-directed monoclonal antibody-drug conjugate consisting of three components:

1) the humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for human

CD79b; 2) the small molecule anti-mitotic agent (MMAE); and 3) a protease-cleavable linker that

covalently attaches the MMAE portion of the compound to the polatuzumab antibody.

Current standard therapy and medical unmet needs:

The current standard of care for the treatment of DLBCL is chemotherapy consisting of rituximab,

cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Approximately 60% of patients are cured with this treatment regimen, however, one-third of patients may develop relapsed/refractory (r/r) disease, leading to morbidity and mortality in patients who have exhausted primary treatment therapies.

3 Salvage therapies may include stem cell transplant if the patient meets certain criteria, followed by high-dose chemotherapy. Less than 40% of patients receiving second line therapies are cured, and median overall survival rates are approximately 6 months. There remains an unmet need for patients with r/r DLBCL.

Benefit Assessment:

The efficacy of Polivy was evaluated in Study GO29365 (NCT02257567). This was a randomized, openlabel, multicenter study that included 80 patients with r/r DLBCL that received at least one prior regimen for treatment of their disease.1 Patients were randomized 1:1 to receive the study regimen which included Polivy with bendamustine and a rituximab product (BR) or BR alone for six 21 day cycles. Efficacy was based on complete response (CR) rate at the end of treatment and duration of response (DOR) as determined by an independent review committee (IRC). Another efficacy measure included IRC-assessed best overall response. In the Polivy plus BR arm (n=40), patients received a median of five cycles, with 48% receiving 6 cycles. In the BR arm (n=40), patients received a median of three cycles, with 23% receiving 6 cycles.1 Results: Twenty-five patients in the Polivy plus BR arm achieved a partial or complete response. Sixteen of these patients (64%) had a DOR of at least 6 months, and 12 (48%) had a DOR of at least 12 months. Ten patients in the BR achieved a partial or complete response, and three of these patients had a DOR lasting at least 6 months, and 2 had a DOR lasting at least 12 months. Benefit outweigh its risks

Regulatory Pathway: Accelerated approval

Pretomanid

Pretomanid is antimycobacterial drug indicated, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). Pretomanid is indicated for use in a limited and specific population of patients.

Mode of Actions

Pretomanid kills actively replicating M. tuberculosis, by inhibiting mycolic acid biosynthesis thereby blocking cell wall production. In addition, under anaerobic conditions, bioreduction of pretomanid generates reactive nitrogen species and results in respiratory poisoning of M. tuberculosis complex

Benefit Assessment;

Approval of this indication is based on limited clinical safety and efficacy data. The primary endpoint was a favorable outcome (absence of bacteriologic failure, relapse, or clinical failure) through 6 months following end of treatment (EOT). The trial is ongoing and at the interim data cutoff of June 29, 2019, the rate of favorable outcomes 6 months following EOT was 89% (95/107), 95% CI [81%-96%] in the Intent to Treat (ITT) population. As of the January 18, 2019 interim efficacy data cutoff, 32/38 (84%) patients had favorable outcomes at 24 months following EOT. The lower confidence limit for success greatly exceeded the prespecified historical control rate of 50%. In addition, a comparison was made to the outcomes to a matched historical control cohort and to the outcomes for XDR-TB reported in the literature. For the matched historical control, favorable outcome was 9/84 (11%) compared to Nix-TB 39/44 (89%), Relative Risk 64.5, 95% CI [9 to 472], p <0.0001. Successful outcomes based on review of the literature for treatment of XDR-TB was 28%, 95% CI [21% to 34%] with regimens that did not contain bedaquiline or linezolid. The contribution of pretomanid, bedaquiline and linezolid to the BPaL regimen was based on studies in the murine model of pulmonary TB. In three studies, the BPaL regimen achieved significantly greater reduction in bacterial lung burden (bactericidal activity) than the 2-drug regimens (BPa, BL or PaL) at the 8-week treatment time points. In addition, fewer mice treated with the 3-drug combination relapsed (sterilizing activity) compared to the BPa and BL regimens. Supportive information was provided from other studies in murine models that showed the contribution of the 2-drug combinations that contained pretomanid.
Regulatory Approval Pathway;
As the NDA is being approved under the LPAD pathway, labeling includes appropriate information to reflect approval in a limited population (Ref. Limited Population Pathway for Antibacterial and Antifungal Drugs, Guidance for Industry).