Status: BLA filing expected

Organizations involved:

Favrille, Inc. – Manuf.; R&D; Tech.; World mark.

MMRGlobal, Inc. – Parent

Sidney Kimmel Cancer Center – R&D; Tech.

biosyn Arzneimittel GmbH – Manuf. other

Boyce Thompson Inst. for Plant Research – Tech.

Bayer Schering Pharma AG – Tech.

Schering AG – Former

Cross ref.: See the GM-CSF entries, particularly Sargramostim (Leukine; #169). See also the entry for Rituxan (rituximab; #115). See also the other products (in the Medical Index) used for treatment of non-Hogkin’s lymphoma (NHL), e.g., Rituxan, Zevalin and Bexxar.

Description: FavId is a B-cell non-Hogkin’s lymphoma (NHL) patient-specific, active anti-idiotypic antibody-based immunotherapy essentially involving construction of a recombinant insect cell (caterpillar)-expressed single-patient tumor-targeted antibody linked to keyhole limpet hemagglutinin (KLH), which increases its immunogenicity, with this recombinant antibody-KLH conjugate then used as an anti-idiotypic vaccine, involving the antibody inducing immune responses against the targeted tumor antigen (patient’s tumor). The treatment process starts by taking a biopsy sample of a patient’s tumor cells and rapidly identifying the unique tumor antigen genes present in their tumor. Idiotypes (Id; unique tumor immunogen-specific epitopes from whole antibodies) are then derived from the variable or antigen-binding portions of immunoglobulin (antibodies) from full antibodies from (expressed by) the patient’s own B-lyphocytes (B-cells), i.e., target tumor antigen-binding portions of antibodies are extracted. Unique antibody gene sequences that correspond to the patient’s tumor are identified, cloned, and inserted into a human immunoglobulin framework sequence, i.e., the derived tumor-targeted epitope region is inserted back into an antibody framework. The gene now encoding a full chimeric Id-specific antibody is inserted into a baculovirus vector, which is used to transform a host continuous insect cell line, which is cultured and expresses the full idiotypic antibody (Id). Once purified, this patient-specific idiotypic protein is conjugating to keyhole limpet hemocyanin (KLH), a large immunostimulatory protein. The resulting Id-KLH conjugate or FavId is administered to the patient combined with Leukine (GM-CSF; see related entry) to enhance its immunogenicity. Note, this is an anti-idiotypic vaccine, with an antibody construct used to stimulate immune responses to the original antigen targeted by the antibody. As a result, a treated patient’s immune responses include specific responses to their B-cell lymphoma.

FavId is used following treatment with existing standards of care (Rituxan; see related entry) to extend time to disease progression, or TTP, in patients with B-cell NHL. FavId enhances the effect of Rituxan, a passive immunotherapy and the market leader in NHL therapy, by stimulating the immune system to recognize the idiotype protein on the patient’s tumor and destroy the tumor cells. Most patients treated with Rituxan relapse within one to three years, so FavID/Id-KLH is used to “train” the patient’s the immune system to recognize and maintain that Rituxan-induced immune response.

Nomenclature: Tumor Antigen-KLH Vaccine, rDNA [BIO]; avId [TR]; Id-KLH [SY]; tumor idiotype antigen, recombinant, personalized–keyhole limpet hemagglutinin conjugate autologous priming of dendritic cells plus granulocyte macrophage-colony stimulating factor (GM-CSF, rDNA) [SY]; idiotype-pulsed dendritic cell vaccination [SY]; B-cell non-Hodgkin’s lymphoma autologous immunoglobulin idiotype-KLH conjugate vaccine [SY]

Biological.: Immunotherapies are designed to use a person’s immune system to fight diseases, including cancer. Immunotherapies enable the immune system to better target and destroy diseased cells, and can have far fewer side effects than other therapies, such as surgery, chemotherapy and radiation therapy. Active immunotherapies are designed to (re)program the immune system to generate a sustained and robust humoral and cell-mediated immune response to tumor antigen(s). Anti-idiotypic vaccines and other active immunotherapies can “teach” the patient’s own immune system to recognize and attack tumors

In the case of B-cell non-Hodgkin’s lymphoma, the antibody protein made by the patient’s B-cell non-Hodgkin’s lymphoma is used as a target for immune attack. The unique antigens in this antibody protein are referred to as the idiotype. The immune system can differentiate between lymphoma cells and normal B-cells based on their idiotype. As a result, following successful idiotype immunotherapy, a patient’s immune response is specific to their B-cell lymphoma.

B-cell malignancies express a unique antigen, the immunoglobulin idiotype (Id), on their surface. Since most B cell malignancies arise from the clonal expansion of a single B cell, all cells comprising a B-cell malignancy expresses a unique Id protein. Hence, idiotypic protein should serve as an ideal target for immune-based therapy of B-cell malignancies, such as lymphoma or leukemia.

The idiotype is the hypervariable region of immunoglobulin which, in B-cell lymphoma is identical on all affected (tumor) cells. This antigen contains protein sequences from both the variable immunoglobulin heavy and light regions (VH and VL). Coupling of the recombinant Id protein to KLH and simultaneous local administration of GM-CSF results in augmentation of tumor-specific immune responses.

Binding of insect cell-expressed Id to the surface of dendritic cells (DCs) has been shown to be much stronger than binding of comparable hybridoma-derived Ids, recombinant mammalian cell-expressed monoclonal antibodies, and KLH. Recombinant proteins produced in insect cells have altered glycosylation patterns (terminal mannose residues) that may further contribute to immunogenicity,

Companies.: FavId was developed, is manufactured and will be marketed by Favrille, Inc., now owned by MMRGlobal, Inc. As discussed in the Tech. transfer section, FavId originated from work performed by Dr. Gold, a company founder, while with the Sidney Kimmel Cancer Center. Favrille has so far retained exclusive worldwide commercialization rights.

KLH is purchased from biosyn Arzneimittel GmbH (biosyn), currently the only supplier of KLH with a related drug master file (DMF) with the FDA. In Nov.2004, Favrille entered into an eight-year supply and license agreement with biosyn for supply of KLH.

In Feb. 2007, Favrille concluded an agreement with Berlex, Inc., a U.S. affiliate of Bayer Schering Pharma AG, concerning use of Leukine (GM-CSF, rDNA) with FavId for treatment of B-cell non-Hodgkin’s lymphoma (NHL). Leukine has consistently been used in clinical trials with FavId.

FavId for clinical trials has been manufactured in Favrille’s 26,000 sq. ft. multi-product cGMP manufacturing facility in San Diego. This pilot facility is housed in a 80,000 square foot building, which is being modified for commercial-scale manufacture of FavId. Upon completion, this facility will produce FavId for up to 4,000 patients/year to meet commercial needs. Favrille expects to be prepared for commercial production of FavId as early as the fourth quarter of 2007.

Manufacture:      Favrille asserts that its manufacturing methods “can allow for a commercially viable product with gross margins similar to those seen for other biopharmaceuticals and enable physicians to use FavId in concert with all existing standards of care for indolent B-cell NHL, including Rituxan.”

As indicated by Favrille’s patents/applications, manufacture of Id-KLH involves a single chimeric protein containing either a VH and/or VL region from an immunoglobulin chain from a B-cell of a patient and an immunoglobulin constant region (Fc). The DNA sequence encoding the variable region of the idiotypic immunoglobulin is cloned using primers derived from the 5’ end of each unique subfamily of light and heavy immunoglobulin chains together with a constant region primer, with cloning by polymerase chain reaction (PCR; or other standard method). The chimeric protein thus comprises a portion of a variable region from an immunoglobulin molecule from a patient and a portion of a consensus constant region. The baculovirus vector generally contains two expression cassettes each having a promoter, a secretory signal sequence and a chimeric protein. One expression cassette contains the baculovirus AcNPV p10 promotor linked to the honey bee melittin secretory signal sequence. The other expression cassette has the polyhedrin promotor linked to a human placental alkaline phosphatase secretory signal sequence. The signal sequences may also be endogenous signal sequences associated with the VH and/or VLgenes isolated from patients or other signal sequences involved in antibody production. The genes encoding the VH or VL portions of the immunoglobulin chains and the genes encoding immunoglobulin constant region are inserted into the expression cassette of the baculovirus vector allowing expression of the chimeric protein(s) in vector-infected insect cells, apparently the High Five Trichoplusia ni caterpillar cell line (licensed from the Boyce Thompson Institute for Plant Research). In a preferred embodiment, the constant region of the immunoglobulin heavy chain, such as IgGgamma1, with either the VH or VL region, is controlled by the polyhedrin promotor. The insect cell-expressed chimeric proteins are purified using affinity columns, e.g., using Protein A, and chemically conjugated to KLH.

Using Favrille’s proprietary manufacturing technology, the entire process from biopsy to treatment can be completed in about 8 weeks, compared to 6 months or more required with other personalized immunotherapy approaches.

Animal protein-free culture media from Expression Systems LLC are used for propagation of insect cells. Expression Systems has submitted a related drug master file (DMF) with the FDA. Favrille intends to qualify a second source for the cell growth media, or will manufacture needed cell growth media in house from commercially available raw materials.

The main barrier to commercialization of this technology has been the difficulties associated with the production of a patient-specific product at a cost that is commercially viable. Favrille has addressed this by developing a proprietary baculovirus-insect cell expression system that can rapidly and cost-effectively produce FavId.

Favrille asserts its manufacturing process has benefits including 1) rapid production cycle, with delivery to patients in eight weeks. This is a number of months shorter than previously reported cycle times for manufacturing idiotype immunotherapies for B-cell NHL. This timeline allows administration of FavId at what Favrille believes to be the optimal time following treatment with Rituxan (see related entry); 2) reliable manufacturing, with no change in the production method for each patient regardless of the number of units of FavId produced. This small-scale unit operation is easily replicated to produce multiple patient therapies simultaneously without the risks associated with traditional scale-up for commercial recombinant protein production; and 3) automation, with the time required to identify the genetic information used to construct the insect-cell expression vector reduced by automation. Favrille believes that many other steps in the production of FavId can be automated.

FDA class: Biologic BLA

Status: Favrille had expected to complete filing of a BLA with FDA in late 2007 or early 2008. The company has a Special Protocol Assessment (SPA) with FDA for its Phase III trial. FavId has received Fast Track designation, allowing submittal of portions of the BLA as they are completed.

Tech. transfer: Patents covering aspects of FavId or Id-KLH therapy assigned to Favrille include 6,911,204, “Method and composition for altering a B cell mediated pathology.” Claims include treatment of B-cell cancers using chimeric immunoglobulin genes isolated from patients’s B-cells and protein manufacture in a baculovirus vector-transformed insect cell line [Trichoplusia ni or Spodoptera frugiperda (Sf9] expression system.

Favrille also holds an exclusive royalty-free license from the Sidney Kimmel Cancer Center to intellectual property developed by Dr.Daniel Gold while he was employed there prior to joining the company. This intellectual property is jointly owned with the Cancer Center, which holds a license for non-commercial research and educational purposes.

Patent applications assigned to Favrille include U.S. 20050238645 (with the first 60 of its 106 claims now cancelled) and 20050202004 (with 59 of its 76 claims now cancelled), both titled, “Method and composition for altering a B cell mediated pathology.” These provide further coverage for FavId. Favrille also has over twenty patent applications pending outside of the U.S.

Favrille’s SEC disclosures note that third party patents that may affect marketing of FavId. These include patents held by Genentech (and City of Hope National Medical Center) relating to the expression of recombinant antibodies (Cabilly II: see the Monoclonal Antibodies entry, #300); patent rights held by Genetope relating to immunotherapy using idiotype proteins produced using T-lymphoid cells for the treatment of B-cell lymphoma; and Schering Corp. (now Bayer Schering Pharma) patents relating to the use of GM-CSF as a vaccine adjuvant for use against infectious diseases. Favrille asserts that Genentech’s Cabilly II patent is not infringed, and that the patent may be invalid and/or unenforceable (but this seems unlikely to prevent Genentech from asserting patent infringement). The GM-CSF-related intellectual property has apparently been licensed by Favrille as part of its agreement with Schering for use of Leukine (see the Companies section above).

Trials: Long-term experience from Phase II trials shows that a majority of treatment-naive B-cell NHL patients who receive FavId following Rituxan induction treatment remain progression-free with a median follow-up of 32 months. This is much longer than the median time to disease progression (TTP) for treatment-naive patients receiving Rituxan alone, even where high overall complete remission rates were also observed.

Enrollment of 349 patients in a pivotal, randomized, double-blind, placebo-controlled Phase III clinical trial of FavId was initiated in July 2004 and completed in Jan. 2006. The trial is evaluating FavId following Rituxan, the current standard of care, for the treatment of follicular B-cell non-Hodgkin’s lymphoma, and it includes both treatment-naive and relapsed/refractory patients with stable or responding disease following treatment with Rituxan. After Rituxan treatment, patients are randomized to receive either FavId with GM-CSF or placebo with GM-CSF. Analysis of the primary endpoint, time to disease progression (TTP), is expected during the fourth quarter of 2007. This trial has received an SPA from FDA.

In Nov. 2006, Favrille reported results from a planned blinded interim analysis of a secondary endpoint in the first 233 patients enrolled in the pivotal Phase III trial. The interim analysis was conducted on 233 randomized patients who had been followed for 12 months or more. The objective response rate (ORR) was first assessed eight weeks following Rituxan induction treatment, at which time it was 64%, with 18% of patients in complete remission. ORR was shown to increase to 70%, with 46% of patients in complete remission. The blinded data showed that 41% of patients who were assessed as stable or in partial remission at the end of Rituxan induction treatment had a response improvement, and 80% of those patients converted from partial to complete remission (i.e., the combined results, including those of placebo recipients are positive, indicating likely efficacy for FavId). The analysis did not demonstrate a statistically significant difference between treatment and control groups in the secondary endpoint of response improvement. Favrille noted, “it is important to remember that the unmet medical need in the treatment of indolent B-cell NHL is the durability of a response. This analysis shows we will have a large number of patients in both partial and complete remission to follow for our primary endpoint of time to disease progression (TTP).”     

FavId has also been tested in several multi-center, open-label Phase II clinical trials involving more than 130 indolent B-cell NHL patients. Long-term follow-up data suggest that the administration of FavId following Rituxan induction therapy extended TTP compared to historical data of Rituxan alone.

Favrille also has Phase II clinical trials of FavId ongoing in other B-cell NHL Indications:.

In results reported by the National Cancer Institute (NCI) in 2005, NHL-specific immune responses were reported for 19 of the 20 patients. With a median follow-up time of 9.2years, 45% of patients remained in continuous complete remission with an overall survival rate of 90%. FavId immunotherapy converted eight of 11 patients tested to a molecular remission, i.e., no evidence of tumor could be seen even at the more sensitive level of DNA detection. The preliminary results from this NCI trial were published in Nature Medicine in Oct.1999, and a more recent update from this trial was published in Blood in Nov.2003.

Disease: The American Cancer Society (ACS) cites non-Hogkin’s lymphoma (NHL) as the sixth most common form of cancer and the sixth leading cause of death among cancers in the U.S. The ACS predicts that there will be about 63,190 new cases of NHL inthe U.S. in 2007, and the NCI has estimated that ~332,000 patients suffer from this disease.

B-cell NHL is a cancer of B-cell lymphocytes, the body’s white blood cells principally responsible for expressing circulating antibodies. About 85% of NHL patients in the U.S. have B-cell NHL, with about half having the indolent form of the disease. Although indolent B-cell NHL is slow-growing, it is incurable with existing therapies and inevitably fatal. The median survival time for patients diagnosed with advanced stages of indolent B-cell NHL is estimated to be between seven and ten years.

B-cell NHL is composed of a diverse group of malignancies with varying patterns of behavior and responses to treatment. Both the prognosis for patients with this disease and their treatment depend on the tumor histologic type and stage. B-cell NHL is commonly divided into two groups: indolent NHL and aggressive NHL. Indolent B-cell NHL has a relatively good prognosis, with a median survival as long as 10 years. Early-stage indolent B-cell NHL can be effectively treated and often cured with radiation therapy alone. Patients with advanced stage indolent B-cell NHL are not considered curable, but generally respond to treatment with a remission. These remissions are generally temporary, and patients require additional treatments when they relapse. Aggressive B-cell NHL has a shorter natural history. Only 50% of these patients can be cured with chemotherapy alone or with combinations of chemotherapy and Rituxan. If patients relapse after treatment, the vast majority of relapses occur in the first two years following therapy.

Medical: Rituxan, Zevalin and Bexxar (see related entries) are now commonly used for NHL treatment. Rituxan is the current standard of care. However, patients eventually relapse, e.g,. typically in 1-3 years for those treated with Rituxan (making them candidates for FavId).

Market: Favrille believes its FavId “cost of production allows for a commercially viable product that will enable physicians to use FavId in concert with all existing treatment options for B-cell non-Hodgkin’s lymphoma, including Rituxan, the current standard of care.” Favrille intends to market FavId itself in the U.S., probably in collaboration with a partner. Outside of the U.S., Favrille plans to establish strategic collaborations for the distribution and marketing of FavId.

Competition: Other companies are developing active immunotherapies for B-cell NHL. Genitope Corp. is conducting a PhaseIII trial of its active idiotype immunotherapy product candidate in patients with follicular B-cell NHL who are in first remission following prior treatment with chemotherapy. Antigenics,Inc. has completed a PhaseII trial evaluating its active immunotherapy in indolent B-cell NHL patients. The NCI is also conducting a PhaseIII trial of an active idiotype immunotherapy in collaboration with Biovest Inc., a subsidiary of Accentia Biopharmaceuticals.

Passive immunotherapies for B-cell NHL, e.g., Rituxan, Zevalin and Bexxar (see related entries) monotherapy, restrict the market for FavId and other active immunotherapies, e.g., insurers may prefer to pay just for monotherapy Other B-cell NHL therapeutics in the pipeline include humanized versions of Rituxan in development by Genentech and GlaxoSmithKline/Genmab, galiximab (CD40 monoclonal antibody) from Biogen Idec, Enzastaurin by Eli Lilly, and Velcade by Millenium.