Biologics Clinical Trials, Research, and FDA Actions

Biotechnol Healthc. 2012 Summer; 9(2): 4–5.

PMCID: PMC3411234

Biologics Clinical Trials, Research, and FDA Actions

Michael D. Dalzell

Cancer research results

Overall survival (OS) is the U.S. Food and Drug Administration’s gold standard in clinical trials of cancer agents and among therapies approved for treatment of people with metastatic cancers, none have extended OS as long as 5 months. Now, for some people with metastatic melanoma, vemurafenib (Zelboraf) may be poised to shatter that ceiling.

In an open-label, phase 2 trial of patients with the BRAF V600 mutation, vemurafenib resulted in a 15.9-month median OS. According to researchers who published the study in the New England Journal of Medicine, OS in patients with metastatic melanoma treated with chemotherapy averages 7 months less than the OS observed in the vemurafenib treatment group.

An analysis is underway of OS data from the BRIM-3 study, a controlled, phase 3 trial that initially reported progression-free survival (PFS) in advance of vemurafenib’s August 2011 FDA approval.

In other notable studies involving oncologic agents: Roche reported “significant” PFS improvement in HER2-positive breast cancer patients given trastuzumab emtansine (T-DM1), a Herceptinchemotherapy single-drug combo, vs. those given lapatinib (Tykerb) and capecitabine (Xeloda). Full data will be reported later this year. Ditto for abiraterone (Zytiga), though Johnson & Johnson teased investors with topline results that showed the drug met PFS and OS endpoints when given with prednisone in chemo-naïve, castration-resistant prostate cancer patients.

Hepatitis C race continues

The push to be first-to-market with an effective interferon-free oral regimen for hepatitis C (HCV) ramped up at April’s European Association for the Study of Liver Disease annual meeting. There, distinctly different mid-stage data were aired for three combinations.

Boehringer Ingelheim said a combination of its BI201335 protease inhibitor and BI207127 polymerase inhibitor plus ribavirin resulted in cures (defined as sustained virologic response, or SVR) in 68 to 82 percent of genotype 1 patients (depending on subtype) at 28 weeks; 71 percent of patients with late-stage HCV and cirrhosis achieved SVR — the first interferon-free viral cures ever shown in these populations. Meanwhile, Bristol-Myers Squibb reported that after 4 weeks, daclatasvir in combination with Gilead’s GS-7977 offered 100 percent SVR in patients with genotype 1 HCV and 91 percent SVR in patients with genotypes 2 and 3. As for Gilead, GS-7977 in combination with ribavirin achieved SVR by Week 4 in 88 percent of genotype 1 patients who completed a 12-week regimen. The news was a bright spot for Gilead, which had disclosed that eight treatment-refractory patients in the trial relapsed after the end of therapy.

Annual Meeting Spotlight

American Academy of Neurology

The multiple sclerosis market is poised to become white-hot with several medications exiting the pipeline this and next year. Late-stage data for two of them made headlines in April at the 64th annual American Academy of Neurology meeting in New Orleans. MS powerhouse Biogen Idec presented detailed data for CONFIRM, the second of two phase 3 trials for BG-12 (dimethyl fumarate). In patients with relapse-remitting MS (RRMS), BG-12 significantly reduced 2-year relapse rates (44 percent vs. placebo twice a day, 51 percent vs. placebo taken 3 times a day) while demonstrating a positive safety profile. In a comparator arm, glatiramer acetate (Copaxone), an MS standby with strong national formulary status, reduced relapse risk by 29 percent vs. placebo. Typically, MS patients face a tradeoff between efficacy and safety, so payers may look favorably on an oral therapy that improves on the standard of care with a relatively low risk of iatrogenic disease — if it’s priced right. Novartis learned that the hard way when it ran into staunch payer resistance to the $48,000-a-year price of fingolimod (Gilenya).

Genzyme reported results of a head-to-head trial of alemtuzumab (Lemtrada) vs. interferon beta-1a (Rebif). Among RRMS patients in the lower-dose Lemtrada arm, 65 percent were relapse-free at 2 years vs. 47 percent of patients given Rebif. Mean disability (measured by the Expanded Disability Status Scale) decreased slightly in the Lemtrada group while disability worsened among Rebif patients. As seen in previous Lemtrada trials, thyroid-related autoimmune responses were the chief safety concern, though investigators said these events were manageable.

Biogen filed an NDA for BG-12 on Feb. 28. Genzyme expects to file a BLA for Lemtrada before the end of the second quarter.

FDA BIOLOGIC AND SPECIALTY DRUG APPROVALS, FEB. 1, 2012–APRIL 30, 2012
Date (type)	Manufacturer	Drug (trade name)	Indication	Administration
New drug applications (NDA)
March 27	Affymax	peginesatide (Omontys)	Treatment of anemia due to chronic kidney disease in adult patients on dialysis	Intravenous or subcutaneous injection (monthly)
SELECTED FDA-RELATED ACTIVITIES, FEB. 1, 2012–APRIL 30, 2012
Manufacturer	Drug (trade name)	Type of drug	Proposed use	Notes
Fast track/priority review designations
Roche/Genentech	pertuzumab	Anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization	Added to a regimen of trastuzumab and chemotherapy in patients with HER2-positive breast cancer	FDA granted fast-track designation Feb. 8 after New England Journal of Medicine article showed 6.1 month median progression-free survival. Overall survival rates had not been released as of May 1.
Gilead Sciences	emtricitabine and tenofovir disoproxil fumarate (Truvada)	nucleoside reverse transcriptase inhibitor	Taken prior to sex to prevent risk of HIV spread	An FDA advisory panel recommended approval for the additional indication. Some AIDS advocacy groups are concerned that misuse of Truvada would result in treatment resistance.
Denials and delays
Amgen	denosumab (Xgeva)	RANK ligand inhibitor, currently indicated for prevention of skeletal-related events in patients with bone metastases from solid tumors	Prevention of bone metastasis in patients with castration-resistant prostate cancer	FDA denied expanded indication April 26 on the basis of safety concerns, and asked for data from adequate and well-controlled trials if Amgen chooses to proceed with sNDA.

RANK=Receptor activator of nuclear factor kappa-ß, sNDA=supplemental new drug application.

Sources: FDA, SEC filings, manufacturers’ news releases and product labeling, FierceBiotech, BIO SmartBrief, wire reports, and weblogs

Earlier in the year, Vertex reported that 11 of 46 genotype 1 patients taking an oral regimen of telaprevir (Incivek), VX-222, and ribavirin had achieved SVR by Week 2 and that 9 of the 11 had no sign of the disease 4 weeks after completion of treatment. Telaprevir plus ribavirin and interferon is indicated for genotype 1 patients

Dueling IL-17 psoriasis drugs

Six biologics now on the market for plaque psoriasis target three aspects of the immune system. The next two could offer yet another new therapeutic target: IL-17.

In separate phase 2 studies published in the New England Journal of Medicine in late March, Amgen’s brodalumab and Lilly’s ixekizumab both significantly bested placebo on 12-week PASI-75 results.

Both have moved on to phase 3 trials for psoriasis. Brodalumab is also under study for asthma and psoriatic arthritis (PsA). Ixekizumab is being evaluated for use in patients with rheumatoid arthritis, PsA, and ankylosing spondylitis.

Did you hear?

An analysis of kidney tumors found that genetic mutations differed dramatically in various tumor areas. The findings, reported in the New England Journal of Medicine, could have profound implications for the effectiveness of targeted therapies. ... Imatinib (Gleevec) and nilotinib (Tasigna) can fight the Ebola virus in petri dishes, according to a report in Science Translational Medicine. ... On Forbes.com, Ed Silverman reveals that Abbott is petitioning the FDA to reject any biosimilars for adalimumab (Humira), on grounds that the FDA would have to give away trade secrets to do so.

Footnotes

All clinical trials described in Drug Track are phase 3, randomized, controlled studies unless otherwise specified.

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