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FDA advisory committee expresses support for three therapies
An FDA advisory panel expressed support for three oncology and hematology drug products during a May 24-25 session.
The Oncologic Drugs Advisory Committee (ODAC) reviewed and voted in favor of approval for neratinib (Nerlynx, Puma Biotechnology) for the treatment of early-stage, HER-2–positive breast cancer, L-glutamine powder (Emmaus Medical) for the treatment of sickle cell disease, and a biosimilar version of Amgen’s epoetin alfa for the treatment of anemia from various causes.
FDA often follows the guidance of ODAC when deciding on drug applications, but the agency is not required to do so.
Neratinib
ODAC voted 12-4 in favor of neratinib — an oral, irreversible pan-HER tyrosine kinase inhibitor — for use as a single agent for extended adjuvant treatment of adults with early-stage HER-2–positive breast cancer who received adjuvant therapy with trastuzumab (Herceptin, Genentech).
The ExteNET study — a multicenter, randomized, double blind, placebo-controlled trial — compared neratinib with placebo in 2,840 women after adjuvant treatment with trastuzumab. Invasive DFS within 2 years and 28 days served as the study’s primary endpoints.
Patients treated with neratinib demonstrated an improvement in invasive DFS at 2 years (94.2% vs. 91.9%; HR = 0.66; 95% CI, 0.49-0.9). An exploratory subgroup analysis showed greater benefit for those with hormone receptor–positive disease (HR = 0.49; 95% CI, 0.31-0.75) than hormone receptor–negative disease (HR = 0.93; 95% CI, 0.6-1.43).
Extended follow-up after 5 years demonstrated an absolute difference of 2.5% between the neratinib and placebo arms (90.2% vs. 87.7%; HR = 0.73; 95% CI, 0.57-0.92).
However, researchers made amendments to the protocol throughout the trial. Specifically, researchers enriched the study population with high-risk patients, shortened the study follow-up from 5 years to 2 years, changed the analysis from event driven to time driven, and introduced extended follow-up to 5 years in a reconsent process.
“These results demonstrated a consistent trend in favor of neratinib; however, given the degree of missing data, the true magnitude of benefit remains uncertain,” Amanda Walker, MD, medical officer for the FDA, said during the meeting.
Diarrhea occurred in 95% of those evaluated, and 40% of patients reported severe diarrhea. An ongoing phase 2 study has suggested that loperamide, an antidiarrheal prophylaxis, may decrease the incidence and severity of diarrhea in this patient population.
“Neratinib-associated diarrhea typically occurs early and diminishes with time, and [it] is manageable with antidiarrheal prophylaxis and patient education,” Hope S. Rugo, MD, professor of breast oncology at University of California San Francisco Medical Center, said during the applicant presentations. “Diarrhea is a common side effect of adjuvant therapies for HER-2–positive breast cancer; therefore, we have to manage diarrhea proactively because, more than any other side effect, it affects tolerability, which is important for adherence to therapy.”
The FDA is expected to make its final decision on neratinib by July 21.
L-glutamine
ODAC voted 10-3 in favor of Emmaus Medical’s new drug application for oral L-glutamine powder for chronic use in adults and children age 5 years and older with sickle cell disease.
A phase 3 multicenter, double blind, placebo-controlled study (GLUSCC09-01) included 229 patients aged 5 years and older (mean age, 21.9 years; 22.3% aged 12 years or younger; 54.1% female; 94.3% black) with sickle cell disease or sickle ß0 thalassemia who had at least two painful episodes within 12 months prior to screening. Patients received oral L-glutamine (n = 151) or placebo (n = 78) for 48 weeks, followed by a 3-week tapering period.
The primary efficacy analysis compared frequency of sickle cell crises — defined as a visit to an ED or medical facility for disease-related pain treated with a parenterally administered narcotic or ketorolac — through 48 weeks.
A median of three sickle cell crisis events occurred among patients who received L-glutamine and four among patients who received placebo (P = .0052).
Premature discontinuation occurred in 36% of the L-glutamine group and 24% of the placebo group. Multiple analyses conducted to overcome this dropout rate showed benefit with L-glutamine, with a 0.4 to 0.9 range in reduction in crises per 48 weeks.
A phase 2 study also showed a trend in favor of L-glutamine over placebo, although the primary efficacy endpoint did not reach statistical significance.
“My ‘yes,’ like many of the [votes], was difficult,” Brian I. Rini, MD, FACP, acting chairman of ODAC and a HemOnc Today Editorial Board member, said during the meeting. “This is clearly a bad disease — worse than cancer in many ways, mostly from a stigma standpoint — and to complete two randomized studies is a major accomplishment. Our job, however, is to recommend approval of drugs not based on desperate need, but based on good data. The data were all there and I think it might be helpful in how we apply this drug clinically if it is FDA approved.”
Safety data from both trials showed the most common treatment-related serious adverse events included sickle cell anemia with crisis (L-glutamine, 66.3%; placebo, 72.1%) and acute chest syndrome (7% vs. 18.9%).
“Had this been a very toxic product, I don’t think this committee would have voted for approval,” Rini said. “But, in essence, it’s a natural product with low risk.”
Epoetin Hospira
ODAC voted 14-1 in favor of Pfizer’s biologics license application for epoetin Hospira, a biosimilar version of Amgen’s epoetin alfa (Epogen/Procrit, Amgen).
The biosimilar is proposed for the following indications:
- anemia due to chronic kidney disease (CKD), including patients on and not on dialysis, to decrease the need for red blood cell transfusion;
- anemia due to zidovudine administered at less than 4,200 mg/week for patients with HIV who have endogenous serum erythropoietin levels less than 500 milliunits/mL;
- anemia in patients with nonmyeloid malignancies who develop anemia from concomitant myelosuppressive chemotherapy; and
- to reduce the need for allogeneic red blood cell transfusions for patients with perioperative hemoglobin levels between 10 g/dL and 13 g/dL at high risk for perioperative blood loss from noncardiac, nonvascular surgery.
“The totality of evidence supports the conclusion that the biologic product is biosimilar to the reference product,” Donald E. Mager, PharmD, PhD, associate professor of pharmaceutical sciences at University at Buffalo, The State University of New York, and an ODAC committee member, said after the vote. “The minor differences weren’t clinically meaningful. ... Based on determination of the biosimilar product, I think there is a strong scientific basis.”
The panel reviewed data from multiple parallel-arm studies — which included 849 patients with CKD (EPOE-10-01, EPOE-10-13) and 129 healthy volunteers (EPOE-14-01) — that evaluated the similarities and differences between epoetin Hospira and epoetin alfa.
In EPOE-10-01, patients with CKD received IV epoetin Hospira (n = 301) or epoetin alfa (n = 304). In EPOE-10-13, patients with CKD received subcutaneous epoetin Hospira (n = 80) or epoetin alfa (n = 86), or maintenance therapy with epoetin Hospira (n = 122) or epoetin alfa (n = 122).
In terms of immunogenicity, both drugs showed similar rates and titers of antidrug antibodies. The rates of treatment-induced antidrug antibodies were 0.4% for both arms of EPOE-10-01, 0% for EPOE-10-13, and 3% for the epoetin Hospira arm and 3.2% for the epoetin alfa arm of EPOE-14-01. During the maintenance period of EPOE-10-13, rates of treatment-induced antidrug antibodies appeared similar between both products (1% vs. 0.9%).
Two clinical studies among healthy individuals (EPOE-12-02 and EPOE-14-01) evaluated the pharmacokinetics and pharmacodynamics — which include reticulocyte count and hemoglobin levels — following single and multiple doses of both products. Both studies met various pharmacodynamics and pharmacokinetics similarity prespecified margins.
Adverse events appeared similar between the products; 75% of patients in both groups experienced at least one adverse event. Common adverse events included nausea, vomiting and muscle spasms.
Although a majority of panel members voted yes based on the established comparability, concerns about immunogenicity and patient populations remained.
“I voted yes but with some hesitation,” Courtney J. Preusse, MA, research administrator in the pathology program at Fred Hutchinson Cancer Research Center and ODAC committee member, said after the vote. “Although I see the cost-effectiveness benefit, I am still concerned and uneasy with the fact that the patient population in which this drug was tested is very small in the United States.”
Thomas S. Uldrick, MD, MS, clinical director of the NCI’s HIV & AIDS Malignancy Branch at the Center for Cancer Research, cast the lone dissenting vote.
“I do not support indications one and four based on the clinical data ... and I have residual concerns about lack of data of immunogenicity and safety data in patients with HIV,” Uldrick said after the vote.
The FDA accepted the application for review in February 2015. However, they initially denied the application approval and issued a complete response letter to Pfizer later that year. – by Chuck Gormley, Kristie Kahl and Melinda Stevens