San Diego – Specifid, a therapeutic agent once poised to be not only be first in class, but first in concept, has failed to meet its primary endpoint in a phase III registration trial of patients with non-Hodgkin’s lymphoma (NHL). This result, announced May 27th has prompted Specifid’s manufacturer, Favrille, to discontinue any further development of the compound. “With respect to getting any useful positive information that would lead to approval out of this data set,” said John Longenecker, PhD, President and CEO of Favrille, “that’s not going to happen.”
Specifid is the second such personalized immunotherapy to be abandoned in the last six months, the other being Genitope’s product, MyVax, which was withdrawn from development last December. Despite that cautionary event, Longenecker had remained confident in his molecule’s ability to perform. “Unlike MyVax, which was expressed in mammalian cells, our patient-specific idiotype (antigen) protein was made in a baculovirus/insect-cell expression system. That meant the protein was only glycosylated with mannose sugars, which is far more antigenic than that produced by mammalian cells.” Specifid was also produced as a nano-particulate formulation, which theoretically allows a patient’s immune system to more easily “see” the antigen. But these distinctions, impressive on the benchtop, bore no statistical significance in the clinic.
In Specifid’s pivotal trial, patients with follicular B-cell non-Hodgkin’s lymphoma were pretreated with rituximab – the current gold standard in this setting – and then randomized in a 1:1 fashion to either Specifid plus GM-CSF (granulocyte-macrophage colony-stimulating factor) or GM-CSF plus placebo (N=349). Following treatment induction, patients with stable disease or disease remission at six months were continued on a maintenance program consisting of the assigned randomized treatment every two months for one year, and then every three months thereafter in the absence of disease progression. The study endpoint was a comparison of times to disease progression for the two treatment arms. Results showed that, even in a mixed cohort of treatment naïve, treatment refractory, and relapsed patients, no clinical outcome was superior for active treatment. “We did a very thorough analysis,” says Longenecker, “All the sub group analysis… we looked at progression as assessed by a number of criteria, but all of the data is consistent and shows no difference between the placebo and treatment arms.”
This newest failure of a personalized therapy is perhaps more striking than the demise of dissimilar novel compounds because an immunotherapy should work in much the same way as a vaccine – of which we have many. As long as the antigen is well defined and consistent, as would be expected in a clonal population of tumor cells, inducing an immune response should be relatively straightforward. So… why isn’t it working? “The short answer is, we don’t know,” admitted Longenecker. He has a suspicion or two, one being the timing of the immunotherapeutic dose after treatment with rituximab – an agent which depletes the B-cell population required for an immune response. Favrille’s strategy was to dose with the active immunotherapy at a time of minimal tumor burden, which would be within a few months of rituximab administration, yet prior to full B-cell recovery. “There’s a theory that you need B-cells to recover from Rituxan in order to get a maximum immune response… but that remains an area of speculation.”
Longenecker is not the only one giving the matter some thought. Investigators at BioVest, makers of the last remaining personalized immunotherapy in development for NHL, BioVaxID, have their own ideas. “We believe the only way to get an effective reaction out of the immune system is to use true copies of the tumor markers,” said Steve Arikian, M.D. Chairman and CEO of BioVest. And this has to be done through the use of hybridoma technology. “You get high fidelity copies of the tumor idiotype (antigen) which is how we got such strong immune response data from our phase II trial.” Arikian wonders if Favrille had the right idea, but the wrong method – their recombinant idiotype product was simply too imprecise to efficiently mimic the endogenous target.
BioVest’s own trial, which began enrollment in 2000, differs for the Favrille investigation in that it used an adriamycin-based chemotherapy to induce the initial disease remission, and the active immunotherapy was only administered after a six month “holiday” in order to allow time for the patient’s immune system to recover. Arikian believes this difference will be critical to producing a significant outcome in the active treatment arm.
The unblinding of BioVest’s trial is slated for late June, yet, even a positive result may not matter. As Favrille’s CEO points out, “We live in a Rituxan dominated world.” The two trials combining immunotherapy with chemotherapy-induced remission were extremely difficult to enroll, and essentially, behind the times. “Genitope took 4 years, and BioVest took 8 years – both programs excluded Rituxan. That will complicate whether [a positive outcome] will find a place in the market.” Rituximab rules. The order of the day is not to rescue chemotherapy, but to find a way to use your drug in a rituximab combination.
For now, Longenecker thinks that anyone looking to enter the patient-specific immunotherapeutic field should first return to the drawing board. Is B-cell recovery necessary? Are T-cells down-regulating a therapeutic immune response? “Our trial has demonstrated that it is possible to develop an immune response against your own idiotype proteins. The question is, how do you take that observation and convert it into a clinically useful approach?”
John McCamant is the editor of the leading investment newsletter Medical Technology Stock Letter. He has established an extensive network of contacts in the investment banking and venture capital communities. His expertise in the field of biotechnology investments is a subject of media interest, and as a result, he is frequently consulted and quoted by The Washington Post, Business Week, Reuter’s, and Worth. In addition, John has been featured on CNN and CNBC. He gave us his thoughts on last week’s release of the ASCO abstracts, and even a little free advice.
OBR: We’ve all heard that this is the first time that ASCO is releasing the abstract data to everyone at the same time. Did you and your team have to pull an all-nighter?
JM: Yes and no. We did spend a lot of time digging through abstracts. However, because we are based on the West coast, we had access at 6 p.m. our time, which meant we could both get a lot of work done and still manage to get some sleep. To be perfectly honest, we are quite pleased that ASCO has “seen the light” and changed their policy to reflect the real world of clinical trial results disclosure. By real world, what we mean is that if nothing else, it is now being acknowledged that ASCO data does affect/move stock prices. In the past, this policy has disproportionately affected the smaller biotechs. The bottom line is that ASCO has a responsibility to disseminate information evenly and fairly, and the changes they made to their policy for this year represents a solid step in that direction.
The new policy makes very good sense, but does beg one question. What was ASCO waiting for? In the past, the abstract books were mailed ahead of the actual conference to ASCO members only. As a result, the accompanying clinical trial data was only available to a select few and individual stocks often began to move. The majority of investors were in the dark as to how this was happening as the information was not yet public. With the new policy, everyone has access to the available information at the same time. All one has to do is look up the abstract on the Web.
OBR: The big news in the late-breakers and plenary session presentations is embargoed until the meeting. Did this year’s batch of abstract data warrant all this attention?
JM: As mentioned above, it was their outdated policy and the fact that no other medical conferences had the same policy that has attracted so much attention. As for the abstracts themselves, they appear to not have had a major effect on stock prices this year. I would guess that it has more to do with there not being a lot of critical or surprising data, and less to do with the playing field finally being leveled. Plenary sessions are chosen for their “juice appeal,” so they should represent some of the most influential/stock moving data. In addition, late breakers will have updated/new information in them that may also be influential. Furthermore, the abstract data is generally from December/January time frame, meaning that many will have updated data at ASCO that is fresh.
OBR: Let’s dig into it, what is your take on some of the highlighted research data released last week. What companies are you focusing on for the upcoming annual ASCO meeting?
JM: We believe that Wall Street usually does a good job covering the bigger names in biotech. The following two companies are not as well covered by Wall Street and represent two of the more attractive investment opportunities within the oncology investment space:
Incyte (abstract #7004) showed data from a Phase 1/2 trial testing INCB18424 in 32 myelofibrosis (MF) patients and patients with post polycythemia veraessential thrombocytopenia myelofibrosis (Post-PV/ET MF) in which all patients were given 25 mg BID. The 25-mg dose was the starting and maximum tolerated dose (MTD)—an expanded cohort of 21 patients has also been enrolled at the MTD. All of these patients have been on drug for at least one month. Two patients had grade 4 thrombocytopenia at 50 mg, which defined the dose-limiting toxicity. This is a normal response to a high dose, and not unlike that seen with other drugs that treat blood cancers. No other significant drug-related toxicities were observed. The key result was a significant and dramatic reduction in splenomegaly, with reductions of 53% at one month (in 24 patients), and 76% at three months (in 7 patients). In addition to improved constitutional symptoms, drug-related effects reduced the dependence on transfusions and resulted in a decrease of proinflammatory cytokines—the so called “cytokine storm” that lies at the core of MF patients’ symptoms. Investigators concluded: “Treatment with [INCB18424] results in unprecedented clinical activity in MF and post-PV/ET MF without significant toxicity.”
Final thoughts: The updated presentation at ASCO will have much more data, maybe as much as four additional months worth, which we believe will result in a strong ASCO for Incyte. The data should serve to stimulate Wall Street’s interest as the company positions INCB18424 for the upcoming pivotal trials.
GenVec’s data from a Phase 1 dose escalation study of TNFerade (abstract #6067) in conjunction with chemoradiotherapy in patients with recurrent head and neck cancer (HNC) are going to be presented at this year’s ASCO meeting. In this trial, eligible patients have locoregionally recurrent, previously-radiated HNC and performance status 0-2. Patients are receiving 5 days of daily radiation along with continuous infusion of the chemotherapy agents fluorouracil (once daily for 5 days) and hydroxyurea (twice daily). (This combination chemo regimen is referred to as FHX.) Additionally, TNFerade is being administered to patients in escalating doses ranging from 4x109 to 4x1011 PU on day 2 of each cycle by direct intramural injection. Three to six patients are entered on each cohort, and treatment cycles are repeated every other week. At the time of the abstract submission, 10 patients (total) had been entered on three dose levels. Dose level 1 was expanded to 6 patients following observation of possibly related dose-limiting toxicity in one of the patients. Subsequent to this, no dose-limiting toxicity was observed, and patients are currently entered on dose level 3. Overall, the toxicities which have been observed in the trial, such as grade 3 mucositis and dermatitis, are not suggestive of an interaction between TNFerade and FHX. Once the MTD has been defined, the dose of radiation will be escalated.
The bottom line at the time of the abstract submission is that it appears as if TNFerade can be added to concomitant FHX-based chemoradiotherapy in the HNC patient population. This is important, because new treatment options are certainly needed. The simple fact is that the prognosis for patients with locoregionally recurrent HNC remains poor, and a high percentage of these patients that are re-irradiated with concomitant chemotherapy end up experiencing disease recurrence. Of course, TNFerade will not only have to show that it can merely be added to chemoradiotherapy. It will have to show that it offers the potential for improved treatment outcomes. To this end, in addition to updated toxicity data from this trial, early efficacy data from the trial are also going to be presented at ASCO.
Final thoughts: We believe that additional efficacy data in the HNC treatment setting will provide further validation of the already impressive results that TNFerade has produced in the pancreatic cancer
treatment setting (its lead indication), and could provide a catalyst for GenVec’s stock.
Today, IMS Health released their predictions for the global oncology industry. According to the forecast, global sales of cancer drugs will grow 12%-15% and reach $75 to $80 billion by 2012, nearly doubling the forecasted growth rate of the global pharmaceutical market (6.4% in 2007). Twelve to fifteen percent growth for the next several years doesn’t jive with the constraints in oncology markets that our industry feels today. There has been remarkable expansion over the last few years (the AWP years?), and in spite of the predicted 12%-15% growth, this industry feels like it is contracting not expanding.
Go west, east, or south of the US. According to IMS, this growth will be driven by the increasing number of cancer patients receiving chemotherapy in Europe, Japan, and North America. Also evidenced is the fact that more patients in emerging markets such as China, Brazil, South Korea, Mexico, India, Turkey, and Russia are getting access to up-to-date targeted therapies. Maybe this explains my instincts. The constraints I feel are real, and the growth that IMS is referring to is coming from ex-US markets.
IMS identifies the following as key dynamics that are influencing the double-digit growth of cancer products through 2012:
• Financial constraints of payers in major markets are leading to increased rigor for selecting targeted therapies – I see, major markets must mean the US. Now this is making sense.
• Improved screening, diagnosis, and access to modern medicines in developing countries – that’s real progress, access being the key in my opinion. Keep it coming.
• New products and combination therapies – of course there is still the tremendous amount of investment and effort to develop new products, some of which may actually make it to market.
• Growth rates for the top markets decrease – finally somebody said it. I knew it didn’t feel like a 12% growth rate here in the US.
Over the next five years, IMS is predicting in its annual forecast that growth will level out due to
• Tapering of current blockbusters - read: Avastin, Herceptin, Gleevec, etc.
• Fewer newer blockbuster medicines - predictive biomarkers may have something to do with this.
• Loss of exclusivity of four oncology products that have annual sales of over $1 billion - inevitable, but let’s get the lawyers on the phone.
IMS also predicts that future growth will be bolstered by the introduction of 25 to 30 new chemical entities between 2008 and 2012. These new entities will help sustain the trend of the expanding patient population being treated with targeted therapies. While many of these new therapies will target the most prevalent tumor types, namely breast and NSCLC, several will focus on late-stage prostate and pancreatic cancers as well as melanoma.
A strong finish. Twenty-five new chemical entities over a five-year period would be excellent progress. So far through ’08 we’ve had two new oncology approvals: Levoleucovorin (not sure if this counts) and Treanda. We’ve got a lot of work to do to get those 25 NCEs on the market, and contributing to predicted growth, by 2012.
Reports like this provoke industry dialogue both pessimistic and optimistic. What does this report invoke in you? In spite of feelings of contraction, the IMS report indicates it is a healthy industry, and the incremental gains found at each ASCO meeting are meaningful for patients, providers, payers, and industry.
Signifying a change from 2007 enrollment trends, small practice oncology groups are enrolling directly in the Medicare Part B competitive acquisition program (CAP), BioScrip and several practices shared with OBR.
In early 2007, the Medicare Part B program’s vendor, BioScrip, reported that oncology scripts were written under the program, but very few oncology practices had signed up. “We had almost 300 internal medicine specialists enrolled in 2006,” said Russell Corvese, a BioScrip administrator. “Many had an oncologist in their practice writing the chemotherapy script.”
In 2008, however, oncologists—including several in the New York City area—enrolled during Medicare’s latest sign-up period, January 1 to February 15, according to BioScrip. This means that some oncologists are choosing to forego buying and billing drugs under the average sales price system (ASP) for their Medicare population and, for the moment, are sending a significant portion of their business to BioScrip.
Across specialties, there are approximately 3000 total physicians enrolled in the CAP. OBR will have an exclusive oncology enrollee breakdown, interviews, and analysis in an upcoming issue.