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FDA reviewers question efficacy, raise safety issues and cite a challenge on Clovis’ rociletinib

The FDA today raised a host of thorny issues for an upcoming advisory committee meeting scheduled to review Clovis Oncology’s ($CLVS) application for an accelerated approval of its non-small cell lung cancer drug rociletinib (Article, FierceBiotech, APR 8, 2016, View Source [SID:1234510595]).

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In an internal review released Friday morning, the agency noted that it wants its group of outside experts to consider whether rociletinib is better than existing drugs on the market, offered its opinion that serious safety issues associated with the drug will require a "black box" warning to patients and added that the agency challenged the company’s use of unconfirmed responses in its data on the drug last fall.

The comparison the FDA is asking for will pit rociletinib directly against AstraZeneca’s Tagrisso, which won an approval last year based on an overall response rate of 59%, far above the final 32% mark that the Boulder, CO-based company has posted for a 625-mg dose of its drug. Tagrisso and rociletinib both inhibit EGFR and are designed to target lung cancers with a T790M mutation.

The agency’s review also notes serious adverse events in the rociletinib studies, singling out hyperglycemia and QTc prolongation leading to Torsades de pointes–a lethal irregular heart rhythm–which should require the black box warning if the drug is allowed on the market.

Significantly, the review includes a timeline on the interactions between the FDA and Clovis execs for this drug, which won the agency’s breakthrough drug designation based on an overall tumor response rate that was reported early on at more than 50%. By last June, though, the response rate reported by the company for its 500-mg dose was 38%.

Then, on November 9, the FDA noted: "During the Mid-Cycle Communication with Clovis, FDA provided an update of the status of the review and communicated significant issues arising from the review. The FDA stated its disagreement with Clovis’ reported efficacy results of the pooled analysis for Studies CO-1686-008 and CO-1686-019. The disagreement was based on Clovis’ inclusion of patients with unconfirmed responses in the efficacy assessment."

Clovis admitted that it was using unconfirmed responses and submitted an update that required a three-month extension of the FDA review. Several days later, the company updated its data for investors, triggering a collapse of its stock price and sparking outrage among its investors over the company’s timing.

In a word, concluded Stifel, the FDA review is "awful" for Clovis. "We think the drug is dead," noted their analysts, with regulators likely looking to stiff-arm the drug until Tiger-3 data are ready in 2018. That would leave Clovis spending a huge sum on a drug with little or no upside on the market. Clovis is likely to stop all studies, Stifel projected, except for a PD-L1 combination that could open a door to a workable combination therapy.

At the beginning of this week, noted cancer drug development expert Kapil Dhingra stirred considerable discussion with a new analysis which questions Clovis’s use of unconfirmed data long after most investigators would have nailed down a final confirmed response. In an interview with FierceBiotech, he charged the company with misrepresenting its data.

"I feel that the efficacy data have, consistently and repeatedly, over many years, been misrepresented," Dhingra told me earlier. "This is not simply a case of gray zones, this is black and white untrue presentation of the data. And it is not just a minor misrepresentation (such as photoshopping a western blot image etc that can get a basic scientist in trouble); the true efficacy is about half of what they represented."

Typically, the FDA’s cancer advisory group would limit themselves to a conversation devoted to a drug’s risk/benefit profile. Recently, practically any drug that offered a clinical benefit could expect an endorsement, even with serious safety issues. But this time around the FDA may be setting the stage for putting off an approval and waiting for confirmatory study data, or at the very least leaving the drug seriously hobbled in a head-to-head market fight with a competitor.

That’s all something that the FDA advisers will get a chance to comment on next Tuesday. It’s also a subject that FDA cancer czar Richard Pazdur could address. I asked him by email earlier this week if he plans to attend the AdComm next week, and in a one-word reply he responded "yep."

Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review.

Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects.
MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol.
There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg).
Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.

Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus.

H.P. Acthar Gel (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, ≥ 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar’s potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus.
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Delcath Announces First CHEMOSAT® Procedures In Turkey

On April 8, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on the treatment of primary and metastatic liver cancers, reported that the Hacettepe University Clinic in Ankara, Turkey has been activated as a treatment center for the Delcath Hepatic CHEMOSAT Delivery System (CHEMOSAT) for the treatment of cancers of the liver (Press release, Delcath Systems, APR 8, 2016, View Source;p=RssLanding&cat=news&id=2155549 [SID:1234510558]). Hacettepe University Clinic successfully completed its first CHEMOSAT treatments in March, and the center represents the first CHEMOSAT commercial location to be activated outside of the European Union.

"We are especially pleased to be expanding access to CHEMOSAT to benefit the thousands of patients in Turkey suffering with these life-threatening cancers of the liver for which there are limited treatment options," said Dr. Jennifer K. Simpson, Ph.D., MSN, CRNP, President and Chief Executive Office of Delcath. "With its high level of clinical expertise, we believe that Hacettepe University can serve as an important hub for CHEMOSAT treatment to patients in Turkey and throughout the region. We are selectively evaluating other markets in the wider European region in order to continue our geographic expansion and the steady growth in clinical adoption of CHEMOSAT as a treatment for patients with cancers of the liver."

Designing therapeutic cancer vaccines by mimicking viral infections.

The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system’s way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.