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.
An expert panel convened in Atlanta, Georgia, December 9th during the 49th annual meeting of the American Society of Hematology. The Biogen Idec-sponsored symposia, titled, “How does drug pricing drive therapeutic choice?” featured presentations from Frank Lichtenberg, PhD, Professor of Business at the Columbia University Graduate School of Business, New York, NY; Sir Michael Rawlins, MD, Chairman of the National Institute of Health and Clinical Excellence, London, United Kingdom; and Peter Bach, MD, Memorial Sloan-Kettering Cancer Center, New York, NY. Linda Bosserman, MD, FACP, President, Wilshire Oncology, Los Angeles, Calif. moderated the panel discussion on the issue of drug pricing.
Pharmaceutical Innovation and Cancer Survival
According to Dr. Lichtenberg, cancer survival rates have increased substantially in the last 50 years. He hypothesized that the development and use of new cancer drugs has made an important contribution to the increase in cancer survival. He tested this hypothesis by examining the relationship between drug vintage (approval year) and cancer survival in four methods of analysis, using four different sets of data.
His analysis revealed that the cancer sites whose drug vintage (measured by the share of post-1990 treatments) increased the most during the 1990s (indicating use of newer drugs) tended to have larger increases in observed survival rates, controlling for other factors…that drug vintage (the share of post-1985 treatments) had a positive and statistically significant effect on both 1-year and 5-year survival rates...that, typically, countries that adopted new cancer agents more rapidly experienced larger declines in their age-adjusted cancer mortality rate…that state reimbursement policies may play a part in cancer survival rates.
The NICE Experience: A total cost of care approach
Sir Michael Rawlins acknowledged Dr. Lichtenberg’s research that 5-year survival rates appeared lower in the UK than in other European countries; however, he emphasized that the UK has recently doubled its investment in healthcare—and these results have intrigued US payers.
Faced with half of the US’s per capita healthcare investment, the UK has chosen to establish a rationing system for allocating healthcare resources. To set limits, NICE weighs a drug’s cost-effectiveness in its coverage decisions and in some cases has said no to paying for certain treatments.
“Sometimes we need to show selective use of a drug, because we’ve felt it’s not cost effective for certain uses,” said Sir Michael.
Of the five oncology treatment-condition pairs NICE has rejected for use since 1999, three were cost-ineffective. “In Britain, the truth is the population doesn’t like the idea of cost coming into the decision, [but] it’s clear we have to do it,” concluded Sir Michael.
How to Pay for Cancer Drugs
Peter Bach, MD, acknowledged that drug prices can be perceived as too high. He offered a mix of regulatory and policy solutions to control prices, while maintaining choice, including:
• Create a forum similar to NICE’s approach to value-based payment.
• Give patients more of an incentive to spend healthcare dollars efficiently.
• Regulators could set prices and pay a fixed amount per healthcare gain.
• Change the sole-source definition for Medicare’s average sales price purposes.
Note: A full length version of this article was published in the January issue of OBR.
At some point—probably in the very near future—there will be a final decision by the U.S. Food and Drug Administration (FDA) about whether Genta’s antisense agent Genasense® (oblimersen sodium) will be approved for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). In the meantime, the review process has become an increasingly tangled web of data, assertions, and upset. Many healthcare professionals feel that the drug warrants approval and that the FDA’s treatment of Genasense has been too harsh.
Among the concerns raised by the ODAC members was their preference for progression-free survival (PFS) as an endpoint. The committee also asserted that the patients likely to benefit had not been clearly identified, and that the potential number of patients who would benefit did not warrant the approval of an expensive drug.
According to Genta, and many CLL experts, the FDA’s rejection of Genasense at that time was, simply, wrong. Patients have voiced their concerns, too.
According to the most recent findings (ASH abstract 751), which have been submitted to the FDA as part of the appeal, patients in the triple combination arm achieved a complete response (CR) rate of 17 percent, compared with a CR rate of 7 percent among patients treated with chemotherapy alone, a statistically significant difference.
The new data may be enough to warrant approval by the FDA. But the larger question of whether the agent should have been approved in the first place still looms, as do issues other than data that may have influenced the original decision.
Regardless of the outcome, the saga of Genasense raises crucial questions about the FDA review process. These issues extend well beyond this one drug: as is widely known, the FDA review of Dendreon’s immunotherapy Provenge® is now under serious investigation.
In its genuine efforts to ensure drug safety, is the FDA preventing drugs from reaching the patients who could be helped? Are there political reasons behind the FDA’s decisions to approve or reject drugs, and if so, what are they? Are drug applications such as these being used to set a precedent, rather than being evaluated for their own merit? Is the FDA weighing cost too heavily in its considerations of benefit?
Numerous CLL patients have already been helped by Genasense, and there is a clear desire among experts and patients alike that this drug be made available. At some point, the outcome of the Genasense application will be made clear. But its hard-to-treat side effects—the questions and issues raised during the review process—remain.
Note: A full length version of this article was published in the January issue of OBR.