Biotech company ImmunoGen, leveraging the targeting ability of antibodies to deliver cytotoxic drugs directly to cancer cells by developing the next generation of antibody-drug conjugates (ADC) with enhanced anti-tumor activity and favorable tolerability profiles, earlier this week announced that it initiated a pivotal trial to evaluate the efficacy and safety of single-agent mirvetuximab soravtansine in patients with platinum-resistant high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, whose tumors express a high-level of Folate Receptor Alpha (FRα) as well as a Phase III study designed to compare the efficacy and safety of mirvetuximab soravtansine vs. investigator’s choice chemotherapy. In these trials, FRα positivity will be defined by the Ventana FOLR1 (Folate Receptor 1/Folate Receptor Alpha) Assay.
“During the last quarter, we moved forward with our registration studies for mirvetuximab soravtansine and advanced our portfolio of earlier-stage candidates, while adapting to meet the evolving challenges of the COVID-19 pandemic,” said Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.
Staying on track
“Our lead program remains on track with the initiation of our pivotal SORAYA trial (NCT04296890) and patient enrollment in our confirmatory MIRASOL trial (NCT04209855) progressing as anticipated. In parallel, we continue to follow our FORWARD II trial (NCT02606305) combination cohorts and we are pleased to have initial data from our bevacizumab (Avastin®; Genentech/Roche) expansion cohort in platinum-agnostic ovarian cancer selected for a virtual oral presentation [during] the annual meeting of the American Society of Clinical Oncology (ASCO) in May 2020,” Enyedy said.
ImmunoGen initiated the SORAYA study, a new single-arm study in platinum-resistant ovarian cancer for women previously treated with bevacizumab, to support accelerated approval for mirvetuximab soravtansine. At the same time, the company continued to open sites and enroll patients in the confirmatory Phase III MIRASOL trial.
“Having generated approximately $98M in net proceeds through a follow-on offering in January 2020, we are in a strong financial position with our anticipated cash runway extended well into 2022. Drawing on the organizational resilience built over the last year, our team has risen to the challenge of COVID-19 to ensure that we can meet the needs of our patients around the globe. We have put in place business continuity plans to allow us to operate effectively in a virtual working environment, actively monitor our progress in our key studies, and rapidly adapt in response to new developments. Through these efforts, we seek to maintain the momentum we have generated in the business throughout 2020,” Enyedy added.
Expanding focus on mirvetuximab soravtansine
Following the failure of the FORWARD I Phase III trial to meet the study’s primary endpoint of Progression-Free Survival (PFS), in March 2019, ImmunoGen said it would be focused on the potential approval and expansion of their lead asset, mirvetuximab soravtansine, the company’s investigational ADC which had received U.S. Food and Drug Administration Fast Track designation in 2018, by the execution of registration and confirmatory studies for the investigational agent and advancing their early-phase product candidates, as well as exploring partnership capabilities.
The rationale to conduct the registration and confirmatory studies was based on the fact that although the FORWARD I did not meet the PFS primary endpoint in the intent to treat patient population (ITT), mirvetuximab soravtansine was, as presented during the annual meeting of the European Society for Medical Oncology (ESMO) in Barcelona, Spain, in September 2019, well-tolerated with a differentiated safety profile, fewer grade 3+ adverse events, fewer drug-related dose reductions/discontinuations and more patients with improved abdominal/GI symptoms compared to chemotherapy. Furthermore, exploratory analyses suggest that the change in scoring method from PS2+ to 10X introduced a population of patients into FORWARD I with lower levels of FRα expression than intended. A subsequent re-analysis of the FRa high population (by PS2+ scoring) demonstrated improved outcomes that correlated with FRα expression, with the strongest treatment effects for all efficacy endpoints in this population. 
In December 2019 ImmuniGen announced that the single-arm SORAYA clinical study could potentially support accelerated approval for mirvetuximab soravtansine in the treatment of patients with platinum-resistant ovarian cancer.
During the 38th annual J.P.Morgan Healthcare Conference, which took place in San Francisco, CA January 13-16, 2020, Mark Enyedy said that the company was optimistic about their restructured portfolio, allowing the company to speed-up the development of mirvetuximab soravtansine for bevacizumab-treated platinum-resistant ovarian cancer patients.
Phase I Forward study and beyond
A pooled analysis from Phase I and the failed FORWARD I study of mirvetuximab soravtansine demonstrated an ORR of 31.4% and mDOR of 7.8 months in platinum-resistant ovarian cancer patients, compared to historical ORRs of approximately 12%.
Based on these results, Enyedy believes replicating these results in the SORAYA study could support accelerated approval. Enyedy believes that this is possible because the SORAYA study is designed with a more favorable statistical plan and better patient selection. This study also allowed the inclusion of patients who received prior treatment with a PARP Inhibitor, drugs that block the repair of broken DNA, which represents a growing segment of ovarian cancer patients as those therapies move further up the treatment paradigm.
The Phase III MIRASOL confirmatory study is also open, with enrollment ongoing. Further expansion of the mirvetuximab soravtansine program includes the phase Ib FORWARD II study testing the combination with bevacizumab or carboplatin in platinum-resistant and -sensitive patients, respectively. Initial safety and efficacy findings from the FORWARD II study, presented during the ESMO 2019 meeting confirmed that the combination of full-dose mirvetuximab soravtansine, carboplatin, and bevacizumab was well tolerated.
Enyedy further said that the company is also enrolling patients in the platinum-agnostic cohort testing mirvetuximab soravtansine and bevacizumab. The company further expects to present updated data from the FORWARD II platinum-sensitive triplet cohort evaluating mirvetuximab soravtansine and in combination with carboplatin and bevacizumab in the fall.
ImmuniGen is also developing ADCs for the treatment of hematological malignancies. One of these agents is IMGN632, a CD123-targeted ADC, which is designed to treat patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare form of blood cancer that has features of both leukemia and lymphoma, and minimal residual disease (MRD+) in acute myeloid leukemia (AML) following frontline induction therapy and combinations. The drug’s target, CD123 is also referred to as interleukin-3 receptor alpha chain (IL-3Rα), which is widely overexpressed in various hematological malignancies, including acute myeloid leukemia, B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm.
IMGN632 includes the humanized anti-CD123 antibody G4723A linked to a DNA indolinobenzodiazepine pseudodimer (IGN) payload.
In pre-clinical studies, IMGN632 demonstrated potent activity AML samples at concentrations below levels that impacted normal bone marrow progenitors. This suggests that the investigational agent has the potential for efficacy in AML patients in the absence of or with limited myelosuppression.
In December 2019, during the annual meeting of the American Society of Hematology (ASH), the company presented preclinical data for IMGN632 in combination with azacitidine (Vidaza®; Celgene) and venetoclax (Venclexta®; AbbVie / Genentech) in relapsed/refractory AML patients. Enyedy expects that the company will be able to share updated information during the annual ASH meeting in December 2020.
“The data presented demonstrated the potential of IMGN632 to offer a new treatment option for patients with AML and BPDCN,” noted Anna Berkenblit, M.D., Senior Vice President and Chief Medical Officer of ImmunoGen.
“With the benefit of a comprehensive assessment of IMGN632’s safety and efficacy across a wide range of doses and two schedules, we have selected a dose and schedule that demonstrate significant anti-tumor activity, favorable tolerability, and the convenience of a short infusion that can be administered in an outpatient setting. Together with the preclinical data on combining IMGN632 with azacitidine and venetoclax presented by our collaborators from MD Anderson, these updated clinical results provide a strong foundation for our ongoing expansion of IMGN632 monotherapy studies in BPDCN, AML, and ALL, and the recent initiation of our trial to evaluate IMGN632 combinations with azacitidine and venetoclax in relapsed and frontline AML, as well as IMGN632 as monotherapy in minimal residual disease positive AML patients,” Berkenblit explained earlier this year.
One of the early results confirmed positive results in heavily pre-treated patients. “We are particularly encouraged by the activity and tolerability of IMGN632 in heavily pre-treated patients, including a 40% ORR in relapsed and refractory de novo AML patients treated at the recommended phase II dose, and the responses in relapsed or refractory BPDCN patients previously treated with tagraxofusp-erzs (Elzonris®; Stemline Therapeutics) and intensive chemotherapy,” noted Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center following the release of the data in December 2019.
The company continuing enrollment in IMGN632 monotherapy and combination cohorts.
Targeting ADAM9 and Another anti-Frα ADC
Among ImmunoGen’s other early-phase asset is an ADAM9-directed ADC (IMGC936), being co-developed with MacroGenics, and a next-generation anti-Frα ADC (IMGN151).
IMGC936 is an innovative ADC targeting ADAM9, a cell surface antigen that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases, which have been implicated in cytokine and growth factor shedding, and cell migration. Dysregulation of ADAM9, also known as MDC9 or meltrin-γ, is overexpressed on multiple solid tumors and has been shown to correlate with tumor progression and metastasis, as well as pathological neovascularization. Scientists at ImmonoGen have demonstrated that anti-ADAM9 antibodies are efficiently internalized and degraded by tumor cell lines, including lines with only modest ADAM9 expression, making ADAM9 an attractive target for antibody-drug conjugate (ADC) development. 
The investigational drug is comprised of MGA021, a high-affinity humanized anti-ADAM9 antibody site-specifically conjugated to DM21C, a next-generation potent, linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable peptide linker. DM21C offers greater stability and bystander activity than other DM platforms.
To maximize the potential for the activity of IMGC936, the M252Y/S254T/T256E (YTE) mutation was introduced into the CH2 domain of the antibody to improve pharmacokinetics by increasing in vivo plasma half-life and exposure. The low drug to antibody ratio (DAR=2) increases the potential for tumor penetration and drug delivery.
“IND-enabling activities for IMGC936 continue on our plan with an IND submission anticipated by the end of this quarter (2020) and we look forward to presenting pre-clinical data on IMGN151, our next generation anti-FRα ADC being investigated [in ovarian cancer and other tumor types] with a broad range of FRα expression, at the virtual annual meeting of the American Association for Cancer Research (AACR) in June,” ImmunoGen’s Enyedy concluded.
Phase III Study of Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in Women With FRa+ Adv. EOC, Primary Peritoneal, or Fallopian Tube Cancer (FORWARD I). NCT02631876
Study of Mirvetuximab Soravtansine in Comb. With Bevacizumab, Carboplatin, PLD, Pembrolizumab, or Bevacizumab + Carboplatin in Adults With FRa + Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD II) NCT02606305
A Study of Mirvetuximab Soravtansine in Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (SORAYA) – NCT04296890
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (MIRASOL) – NCT04209855
Study of IMGN632 in Patients With Relapsed/Refractory AML, BPDCN, ALL, Other CD123+ Hem Malignancies – NCT03386513
IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia – NCT04086264
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