Over the last couple of days we've heard a lot about the failure of Nexavar in NSCLC. We’ve heard that as Nexavar’s potential in NSCLC diminishes, Avastin establishes itself as an even more important product for NSCLC patients. At the same time we’re hearing a lot about the looming FDA decision on Avastin in metastatic breast cancer. Maybe it’s too much of a stretch, but I see some sort of connection here.
Nexavar and Avastin are not that dissimilar in terms of mechanism of action. Nexavar is a targeted therapy with two indications that couldn’t meet the overall survival endpoint in NSCLC, and Avastin is a blockbuster targeted therapy with multiple indications that didn’t meet the overall survival endpoint in metastatic breast cancer in their registration study. Maybe the connection is in the study design. So why did Bayer/Onyx include squamous cell patients in their NSCLC study? The Genentech people decided not to include them in the NSCLC registration study for Avastin. If the study was positive Bayer/Onyx would have a population of patients that Avastin doesn’t have, but perhaps that design flaw is responsible for the negative outcome of the study (they say publicly that the squamous cell sub-group had a higher death rate). It doesn’t really matter now except as a learning point for people that design NSCLC clinical trials.
The point is that the roller coaster of cancer drug development couldn’t be in a stranger place today with one targeted therapy failing its registration study and the other a couple of days away from a possible monumental regulatory decision. At the minimum, we will all learn a lot this week about study design, FDA trends, and investment opportunities.
If the FDA decision regarding Avastin for breast cancer is negative, oncologists will have lost access to a great targeted therapy and who knows what will happen with insurers and the 25% market share Avastin already has in metastatic breast cancer. If the FDA decision for Avastin is positive, consider it an admission from the FDA that progression free survival can hold its own and may be equally important as overall survival. That is a precedent which I’m sure the FDA is struggling with.
Nobody in the media is making any predictions, so I’ll open myself up. My prediction is…the FDA will delay their decision on Avastin for 60 days and will wait for more study results, or just use the time to solidify their position. Do you want to make a prediction?
The Canadian biopharmaceutical company Helix BioPharma is focused on the development and commercialization of innovative cancer therapeutics, specifically protein therapeutics for cancer. Founded in 1995 through a series of mergers, Helix BioPharma is publicly listed on the Toronto Stock Exchange as HBP. Based on its proprietary core technologies, Helix’s two key initiatives are Topical Interferon Alpha-2b, a treatment for the prevention of the development of cervical cancer that is caused by the numerous strains of HPV; and L-DOS47, an enzyme that specifically targets the environment surrounding lung adenocarcinoma cells to create an anticancer effect.
Helix’s Biphasix™ technology is specifically designed for moving large molecules across the skin/mucosal tissue. The Topical Interferon Alpha-2b cream is designed to deliver interferon alpha-2b molecules to the basal epidermal layer and help prevent HPV infections from potentially leading to cervical cancer.
OBR: Why HPV?
JD: HPV affects 20 million people in the U.S. alone. Once a woman contracts HPV she can develop potentially pre-cancerous lesions of the cervix that may or may not progress to cervical cancer. These lesions are basically abnormal cervical tissue that are dysplastic in nature and, if not resolved, can progress to cervical cancer. The lesions themselves are occurring at a rate of one million abnormal pap smears per year in the U.S. with similar numbers in Europe. Currently, there is no pharmaceutical therapy for these patients and when you look at the numbers involved, we think there is a significant unmet medical need here.
OBR: Right now, what happens when an abnormal pap smear occurs?
JD: There’s a mandate that doctors have to follow in the U.S. and Canada before prescribing a treatment. The only currently available treatments have to be administered in a hospital-type setting because they are surgical or interventional in nature. In mild cases, doctors can use laser surgery or use cryotherapy (freezing) to remove the lesions. In more advanced cases, a LEEP excision is usually performed or a conization which is the removal of abnormal tissue from the cervix. However, in all of these procedures, a battery of side effects can occur that doctors and patients would like to avoid. Side effects can be abnormal discharges, infertility or even pre-mature labor. In lieu of these types of procedures, we hope to provide doctors and patients with a pharmaceutical treatment option.
OBR: Have you completed any clinical studies with Topical Interferon Alpha-2b?
JD: In 2007, we completed a small Phase 2 study in women with HPV-induced low grade squamous intra-epithelial lesions (LSIL) and recorded positive findings. This was a four-center study that included 41 women: 20 in the treatment group and 21 in the control group. The women were treated for 6 weeks with a follow-up at 12 weeks. We showed resolution—meaning that pap smears went from abnormal to normal with no evidence of dysplasia, even upon colposcopy, in just under half of the patients that received treatment versus those patients that received no treatment. It was aggressive therapy and our docs were pretty amazed with the results. This has set the stage for the next phase of trials. That’s the plan. We’re moving to randomized, double-blind, placebo-controlled trials.
OBR: What is your L-DOS47 initiative?
JD: We have developed a product to modify the microenvironment associated with cancer cells. Cancer cells in any given solid tumor exhibit certain traits, including an acidic extra cellular compartment. This compartment has an abnormally low pH level as a result of the metabolic function of cancer cells. Healthy cells, in comparison, are more alkaline in nature. The difference in acidity is thought to play a role in a cancer cell’s ability to invade and metastasize. So we decided to develop a therapeutic that will change that environment from acidic to alkaline.
OBR: Do you have a core technology for that as well?
JD: Yes. DOS47 is the general substance that we want to get to the site of the cancer cell in order to reverse the acidity. To achieve this, we’ve conjugated DOS47 with an antibody fragment specifically designed to target the lungs, and we call it L-DOS47. L-DOS47 is an i.v. product that has incredible specificity for NSCLC cells, and doesn’t bind substantially to healthy tissues or any other cancers for that matter. Once you get DOS47 to the site of the tumor, its activity is extra cellular in action.
Many of today’s compounds have to penetrate the cancer cells in order to function. We’re interested in parking L-DOS47 on the external surface of the cancer cell, where the antigen binding site is for the L-antibody, and then allowing it to cause a biochemical reaction that will modulate the acidity to become alkaline. In addition, L-DOS47 is believed to cause the production of ammonia molecules which readily diffuse into cancer cells and have a cytotoxic effect.
In theory, we think the move from an acidic to alkaline microenvironment has a combination of effects that debilitate the ability of the cancer cell to metastasize and invade. In addition, the cancer cell can’t be supported in an alkaline environment. L-DOS47 is still in the pre-clinical stage, but our goal is to file an IND and move to Phase 1 trials this year.
OBR: Are you looking to partner with your technology?
JD: We’ve already partnered with Schering-Plough to develop Topical Interferon Alpha-2b. With L-DOS47, because of its behavior in reversing acidity and moving to alkalinity, we think there is very strong commercial partnering potential for adjunct application where it would be used with some of the leading therapeutics for NSCLC. We’ll look to evaluate those in time, for now we are coming out of the Canadian woodwork so to speak.
On behalf of OBR, author Bryan Cote contacted 1000 oncology practices via a private e-mail survey featuring 10 questions. Disseminated in September 2007, 104 oncology practices responded; of which 68 were practice managers, 21 physicians, 11 pharmacists, and 4 administrative/billing managers. In October, the author followed up with 20 of the 104 respondents by telephone, 14 oncologists and 6 practice managers, to gather more in-depth responses. Following is a discussion from one of the findings.
Roughly 60% of oncology drug usage can be considered off-label, and inefficiencies have been an unfortunate staple of the compendia-based reimbursement process, affecting the entire oncology-care continuum. Armed with evidence that outdated compendia can negatively affect healthcare system costs and care, payers at the federal and commercial level are beginning to respond with policies more favorable to the oncology business. For all their inherent value as a patient access benefit and reimbursement bridge to new FDA approved uses and indications for patients with cancer, drug treatment compendia recommendations and interpretations have at times been as wildly inconsistent as Phil Mickleson’s tee shots.
In a unique move, that if successful could become a model among other payers, United Healthcare (UHC) is expected to adopt the NCCN Drugs and Biologics Compendium and its recommendations as it’s only accepted commercial business compendium. However, endorsing only one compendium carries with it some potential limitations. According to Gerald McEvoy, PharmD, Assistant Vice President of Drug Information and Editor of the American Hospital Formulary Service (AHFS-DI), the NCCN compendium does not carry guidelines for several orphan cancers. Moreover, unlike the AHFS, which updates its compendium monthly and addresses non-oncology uses for cancer drugs, the NCCN's compendium does not.
Is a Single Compendium a Conflict?
“For everyday guidance,” says Myron Goldsmith, MD, who peer reviews oncology treatment plans as chief medical officer for New Century Infusion Solutions, “NCCN keeps incredibly current…but it’s not as evidence-based as ASCO.”
AHFS sees other issues: “NCCN's scope is far more limited than AHFS’s compendium,” says McEvoy. “Notably absent is [its] focus on medication safety.”
The AHFS is published by the American Society of Health-System Pharmacists® (ASHP) with no apparent vested interest in any one patient population or disease. In its comments to CMS on the Medicare Part B proposed rule, the ASHP strongly recommended that safety information be added to its list of desirable characteristics for a drug compendium. However, there was no mention of this in the final Medicare physician fee schedule rule for 2008.
According to the 2008 Medicare physician fee schedule, there is really only one authorized compendia for Medicare in 2008—AHFS—and so CMS is seeking suggestions, using MedPAC criteria to decide which compendia it will use for the Part B program.
Although the 104 responding facilities represent a small segment of the total market, the insight from both practice managers and clinicians give us some ideas of how to improve the compendia business. Compendia is no doubt a key reimbursement ingredient for providers, but with different compendia recommending different guidelines, and payers relying on multiple compendia, payment for anti-cancer treatment is a time consuming puzzle. And, by only having one approved compendium there will be less sources to help in the approval of off-label usage and more hesitancy to prescribe off-label which is a detriment to patients.