GlaxoSmithKline’s Arzerra flunks lymphoma trial

GSK has missed out on a big new market for its blood cancer drug Arzerra. Approved to treat chronic lymphocytic leukemia (CLL), Arzerra (ofatumumab) failed to pass the test in a B-cell lymphoma trial.. Arzerra was pitted against Roche’s Rituxan (rituximab) in  patients with B-cell lymphoma. The Arzerra-plus-chemo combination didn’t beat the Rituxan-plus-chemo combo on progression-free survival.

Though Arzerra patients fared about as well as Rituxan patients in terms of serious side effects, the Arzerra group did suffer more dose interruptions and delays because of infusion reactions and elevated creatinine levels. It’s a setback for Glaxo’s oncology business, which the company recently agreed to sell to Novartis for up to $16 billion. In announcing that deal, Glaxo believed the company’s cancer portfolio would be in better hands at Novartis, which has greater depth in cancer research and a broader range of drugs. Novartis is adept at developing new indications for existing drugs, and Arzerra is currently under study for other indications, including follicular lymphoma.

As far as CLL goes, Glaxo has had some recent success with Arzerra. Approved in 2009 for relapsed CLL, the drug nabbed FDA approval last month as a first-line treatment. The first-line approval applies to patients who can’t take a common chemo treatment, fludarabine. But earlier this year, Johnson & Johnson’s  new blood cancer treatment Imbruvica beat Arzerra at second-line treatment for CLL.

Researchers deliver low doses of siRNA to lung endothelial cells. PART2

Ironically enough, the polymer-based nanoparticles did not deliver siRNA to liver hepatocytes, the target of many of the experimental therapies being developed by RNAi specialist Alnylam . According to the MIT news release, the researchers were able to block two genes associated with lung cancer and retard the growth and spread of lung tumors in mice through the successful delivery of siRNA to targets in the lung. Andrew Fire and Craig Mello won the Nobel Prize in 2006 for the discovery of the RNAi pathway by which siRNA binds to specific messenger RNA molecules and prevents them from producing a protein, thereby inhibiting gene expression.

However, delivering siRNA to specific cells and organs in the body has proven to be a challenge for therapies that seek to using the pathway to treat diseases. Liver cells have proven to be the easiest targets so far, but the MIT researchers have shown that it is possible to target other organs and with low doses of RNA, reducing side effects. Indeed, Novartis’ attempt at RNAi drug development failed because it targeted oncogenes that are ubiquitously expressed, or expressed in tumor cells, and that’s not where delivery is optimized.Clearly, Big Pharma and others interested in commercialization should read the Nature Nanotechnology paper closely for tips.

Researchers deliver low doses of siRNA to lung endothelial cells Part 1

One of the chief drawbacks of RNA interference (RNAi) therapies so far has been the difficulty of delivering small interfering RNA to cells outside the liver. That’s why the breakthrough from researchers at the MIT in delivering siRNA to endothelial cells in the lung and other organs is a big deal. The researchers screened 2,400 nanoparticles containing siRNA in cervical cancer cells by determining if they could silence a gene for a synthetically added fluorescent protein. Next, the winning particles were tested in endothelial cells by determining if they could interfere with a gene called TIE2. The method is described in greater detail in the May 11 issue of Nature Nanotechnology.

Crucially, and of great clinical significance, the researchers were able to reduce gene expression by more than 50% using a dose 100 times smaller than the existing standard for endothelial delivery, according to MIT. The delivery method performed best in the lungs but also worked in the heart and kidney as well as other organs–encouraging, but not terribly surprising given that endothelial cells line the inner walls of the blood vessels of many organs.

ATP-Mediated Liposomal Drug for anticancer

A paper, Enhanced Anticancer Efficacy by ATP-Mediated Liposomal Drug Delivery, is published online in Angewandte Chemie.Biomedical researchers have developed an anti-cancer drug delivery method that essentially smuggles the drug into a cancer cell. The method can be likened to keeping a cancer-killing bomb inside a cancer cell. This is an efficient, fast-acting way of delivering drugs to cancer cells and triggering cell death. Researchers also used lipid-based nanocapsules that are already in use for clinical applications.

The technique uses nanoscale lipid-based capsules, or liposomes, to deliver both the drug and the release mechanism into cancer cells. One set of liposomes contains adenosine-5’-triphosphate (ATP). A second set of liposomes contains an anti-cancer drug called doxorubicin (Dox) that is embedded in a complex of DNA molecules. When the DNA molecules come into contact with high levels of ATP, they unfold and release the Dox. The surface of the liposomes is integrated with positively charged lipids or peptides, which act as corkscrews to introduce the liposomes into cancer cells.

As the liposomes are absorbed into a cancer cell, they are sealed off from the rest of the cell in an endosome. Two other things are happening simultaneously. First, the ATP liposomes spill their ATP into the Dox liposomes, releasing the Dox from its DNA cage. Second, the walls of the Dox liposomes create an opening in the endosome, spilling their Dox-rich contents into the surrounding cell and leading to cell death.

Researchers found that the new technique significantly decreased the size of breast cancer tumors compared to treatment that used Dox without the nanoscale liposomes. This liposome-based technique allows us to introduce additional ATP into the cancer cell, releasing the drug more quickly.

Merck halts study of the cancer drug vintafolide

Merck  and partner Endocyte  have stopped a late-stage study of the ovarian cancer-treating vintafolide on the advice of a data safety monitoring board.. Reviewing vintafolide’s Phase III results in an interim analysis, the board recommended that Merck halt its trial for futility. Vintafolide, which Merck picked up in a licensing deal worth up to $1 billion, is a targeted treatment for platinum-resistant ovarian cancer, and its promising Phase II performance in that indication was enough to sway European regulators to recommend conditional approval back in March.

The drug’s Phase III stumble has wiped away much of the cheer tied to that regulatory win, a story borne out in Endocyte’s share price: The biotech soared more than 175% on the European Medicines Agency’s favor, but it has now fallen roughly 60% in premarket trading after Friday’s announcement. Merck never publicly committed to a Phase III trial in that indication, and it remains to be seen whether vintafolide’s ovarian cancer futility will change the company’s plans. Merck didn’t respond to a request for comment on Friday.

In any case, the latest news is a major setback for Merck as they try to right the ship of research. Vintafolide, was the second prong of Merck’s late-stage cancer pipeline, following the promising immunotherapy MK-3475.

BTK in Cancer PART3

The only other BTK inhibitor with sufficient data to infer this is AVL-292 [CC-292] and this agent does not look as good. This very well may be a defect in the drug and not the target. Other second- generation molecules are coming forward that do look quite good and this has the potential to make the field very similar to CML where we have several tyrosine kinase inhibitors that can really help patients.

Key questions are going to relate to the mechanisms of resistance, and how those will influence our decisions about whether to use BTK inhibitors sequentially or in combination with other novel agents. So far, some early reports suggest that mutations of the target cysteine in BTK are a cause of relapse, so it is plausible that dual pathway inhibition with another targeted agent might suppress the development of such clones. In addition, we will need to determine if BTK- independent clones may grow out as a mechanism of resistance.

The most significant questions are: What is the role of tumor microenvironment versus direct tumor effect? What are the immune-modulating effects of BTK inhibitors and is this predominantly on the BTK or ITK target? How do we combine these in a rational way to cure CLL and other diseases?

BTK in Cancer part2

Ibrutinib is a drug for CLL where patients can be treated with an oral agent for extended periods of time without relapse or toxicity that has been observed to date. It has newly identified immune-modulating potential, which mayexplain the dramatic efficacy. As moving forward to upfront therapy of CLL, it is potentially possible that we will see a pattern of treatment emerge that is similar to chronic myeloid leukemia (CML). This is particularly true for elderly patients and those with other comorbidities. This agent truly is a patientfriendly therapy.

The data in mantle cell lymphoma led to the initial approval by the FDA. In addition, a Breakthrough Therapy designation was given for ibrutinib in Waldenström’s macroglobulinem. Ibrutinib has been effective across a wide range of B-cell lymphomas including follicular lymphoma, mantle cell lymphoma, monocytoid B-cell lymphoma, DLBCL, and Waldenström. The best data emerge from the lower-grade non- Hodgkin lymphoma. It is now being explored in multiple myeloma, graft-versus-host disease, and many other diseases. Its greatest potential as an immune-modulating agent based upon its ability to inhibit a kinase called ITK.

Two other agents are in phase I clinical trials that were recently updated at ASH, and these are CC-292 and ONO-4059. Both are also covalent inhibitors of BTK that bind to the same cysteine residue, but CC-292 in particular is more specific than ibrutinib for BTK. CC-292 is furthest along and appears safe and efficacious at the recommended phase II dose, but we do not yet know about its durability. ONO-4059 also looks promising in dose escalation studies but patient numbers are thus far limited and follow-up is short.

For startup bio-pharma companies, clinical trial failure = stock value diminishment

Startup bio-pharma companies are extremely over-valued in term ofstock price, simply because of the potential investment return from success of their clinical trials. Once these trials fail, the company’s value plunges significantly. Here is the latest example of it.

Merck (MRK), known as MSD outside the United States and Canada, and Endocyte, Inc. (ECYT), today announced that the Data Safety Monitoring Board (DSMB) of the PROCEED trial has completed a pre-specified, interim futility analysis and the DSMB recommended that the trial be stopped because vintafolide did not demonstrate efficacy on the pre-specified outcome of Progression-Free Survival (PFS) in patients with platinum-resistant ovarian cancer. As a result, the stock price of Endocyte, Inc dropped by 62% overnight.

The DSMB did not identify any safety concerns for the patients enrolled in the trial. Based on the DSMB recommendation and while further review of the data is conducted, the Companies have taken steps to notify investigators that screening and randomization of participants in the trial will be suspended.

PROCEED is a Phase 3 randomized, double-blind clinical trial, evaluating vintafolide in combination with pegylated liposomal doxorubicin (PLD) compared to PLD plus placebo for the treatment of folate receptor-positive, platinum-resistant ovarian cancer. The primary endpoint of the trial was PFS as measured by RECIST v 1.1 (Response Evaluation Criteria In Solid Tumor) criteria in patients with all target tumor lesions positive as assessed by etarfolatide imaging agent.

Alexion Pharmaceutics wins FDA accelerated approval ofSoliris® (eculizumab) for the Treatment of Patients with aHUS Part 2

“We are pleased that, since 2011, the FDA’s Accelerated Approval process has enabled us to provide Soliris to individuals whose lives have been at risk of the severe clinical manifestations of aHUS and who would otherwise have had no safe or effective treatment options,” said Leonard Bell, Chief Executive Officer of Alexion. “The results obtained from the two additional prospective clinical trials further confirm the safety, efficacy and life-transforming benefit of chronic Soliris treatment in both adult and pediatric patients with aHUS. The updated label now includes data that specifically supports the longer-term benefit associated with chronic and sustained Soliris treatment. We continue to work with a sense of urgency to bring Soliris to more patients suffering from this life-threatening disease worldwide.”

The Clinical Studies section (Section 14.2) of the revised Soliris prescribing information now includes results from a total of four prospective, single-arm studies in patients with aHUS, three in adult and adolescent patients and one in pediatric patients, as well as one retrospective pediatric study, which evaluated the safety and efficacy of Soliris for the treatment of aHUS. Longer-term data of original registration studies demonstrated that chronic and sustained Soliris treatment inhibited complement-mediated TMA and resulted in significant and continuous time-dependent improvements in renal function, and was well tolerated. Importantly, 5 out of 18 patients in the original registration studies who deviated from the approved Soliris dosing, including discontinuation, experienced severe TMA manifestations whereas patients who stayed on therapy had complete inhibition of complement activity, which was sustained through 2 years. Results from the two additional prospective trials conducted by Alexion – one in adult and the other in pediatric patients with aHUS – showed that Soliris inhibited systemic complement-mediated TMA (the formation of blood clots in small blood vessels throughout the body), improved renal function, decreased or eliminated the need for dialysis and was well-tolerated.2,3 Efficacy and safety results from the additional prospective clinical trials were consistent with those observed in the original Soliris registration trials.

Alexion Pharmaceutics wins FDA accelerated approval ofSoliris® (eculizumab) for the Treatment of Patients with aHUSPart 1

Alexion Pharmaceuticals, Inc. (Nasdaq:ALXN) today announced that the U.S. Food and Drug Administration (FDA) has approved the Company’s supplemental Biologics License Application (sBLA) providing regular approval for Soliris® (eculizumab) for the treatment of adult and pediatric patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). This update reflects Alexion’s fulfillment of post-marketing requirements, including the submission of confirmatory data from two additional prospective clinical trials, including one in pediatric patients with aHUS. The revised label now specifies important longer-term clinical benefit associated with chronic and sustained Soliris treatment with inclusion of results with two years of ongoing treatment in aHUS patients. The updated label also includes data on the use of Soliris treatment prior to use of supportive care with either plasma exchange or plasma in prospective clinical trials.

aHUS is a genetic, chronic, ultra-rare disease defined by immediate and lifelong risk of thrombotic microangiopathy (TMA) resulting in vital organ failure and premature death. Soliris, a first-in-class terminal complement inhibitor, specifically targets uncontrolled complement activation, and is the first and only approved treatment for pediatric and adult patients with aHUS in the United States, European Union, Japan and other countries. Soliris previously received Accelerated Approval (Subpart E) for this indication from the FDA in September 2011. The FDA grants Accelerated Approval to drugs based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit. To achieve regular approval, a drug company must usually submit additional data to verify clinical benefit.