CEA x CD3

Roche removed schizophrenia candidate ralmitaront from its midphase pipeline. Roche’s vision of developing an oral diabetic retinopathy treatment has taken a hit, with the drugmaker stopping development of vicasinabin after completing phase 2. The CB2 agonist was discarded (PDF) as part of a cull that also saw Roche pull back from its CEAxCD3 bispecific candidate cibisatamab. Vicasinabin, also known as RG7774, entered phase 2 in 2020. Roche pitched the candidate as a potential oral alternative to existing invasive treatments, such as injections into the eye, for a condition that leads to vision loss and blindness in some people with diabetes. However, the clinical trial, which finished in July, failed to persuade Roche to keep investing in the candidate. The action eliminates one of the leading oral contenders in diabetic retinopathy. Ocuphire Pharma has an oral candidate, APX3330, that has cleared phase 2. Bayer, InflammX and Rezolute also have oral, clinical-phase assets. Other companies, notably Boehringer Ingelheim, have swung at the indication and missed.  Roche dropped vicasinabin from its pipeline as part of a third quarter cull that also affected cibisatamab, a bispecific designed to bind to CD3 on T cells and CEA on cancer cells. Multiple companies have zeroed in on CEA as an attractive solid tumor drug target. Roche started a phase 1 trial of an older CEAxCD3 bispecific, RO6958688, in 2014 and followed up by taking cibisatamab into the clinic in 2019. The trial evaluated cibisatamab, also known as RG7802, in combination with Roche’s checkpoint inhibitor Tecentriq in colorectal cancer patients. Now, Roche has removed RG7802 in solid tumors from its phase 1 pipeline. The drugmaker continues to assess RG7802 in combination with RO7122290, a bispecific antibody-like fusion protein that simultaneously targets 4-1BB and FAP, in colorectal cancer.     Asked by Fierce Biotech about the pipeline changes on a conference call with the media this morning, Teresa Graham, CEO of Roche Pharmaceuticals, said: “I think these are both very early-stage assets that currently sit in our research and early development organizations.” “We've seen encouraging early data that would lead us to believe that further study is necessary or warranted,” Graham added. “So I would say stay tuned, and hopefully at an upcoming medical conference we'll have more data that we can share.” Roche also removed the schizophrenia candidate ralmitaront from its midphase pipeline. The company terminated a phase 2 trial of the asset earlier this year after an interim analysis found it was unlikely to meet the primary endpoint. Roche terminated another trial of the molecule last year.

Pictured: Roche tower in Switzerland/iStock, olli0815 Roche is eliminating four clinical programs amid drooping sales brought about by a sharp decline in demand for COVID-19 products and a strong Swiss franc, the pharma group announced Thursday morning in its third-quarter earnings results. According to a development pipeline document released alongside the quarterly report, Roche will end a Phase I solid tumor trial for its investigational CEA/CD3 bispecific antibody cibisatamab. The company will also stop Phase II trials of its antipsychotic drug candidate ralmitaront in schizophrenia and the developmental cannabinoid receptor agonist vicasinabin in diabetic retinopathy. Roche discontinued the mid-stage study of ralmitaront after it failed a Phase II trial in May 2023, unable to elicit significant improvements on negative symptoms in a preliminary analysis. The vicasinabin and cibisatamab programs were likewise scrapped following underwhelming reviews of their efficacy in their respective studies. However, in a media call Thursday morning, a Roche spokesperson said that these two candidates were still in the very early stages of development and have shown “encouraging early data” warranting further investigation, Fierce Biotech reported. Roche on Thursday also axed a Phase III study of its leukemia therapy Venclexta (venetoclax) in relapsed or refractory multiple myeloma. Last month, the BCL-2 blocker failed to significantly boost progression-free survival when given in combination with dexamethasone, compared to pomalidomide plus dexamethasone. Overall survival was better in patients treated with the Venclexta-based regimen, but it also fell short of statistical significance. Venclexta was first approved in 2016 for the treatment of chronic lymphocytic leukemia with 17p deletion and has since also been authorized for acute myeloid leukemia. Roche is developing and commercializing Venclexta together with AbbVie. The pipeline culling comes as Roche sustains a slight dip in sales. From January to September 2023, the pharma group made over $49 billion, compared with $52.48 billion during the same period in 2022. At constant exchange rates, this corresponds to a small 1% revenue growth—but with the strong appreciation of the Swiss franc represents a 6% decrease. Much of this decline was driven by the “significant drop in demand” of COVID-19 tests, which resulted in an 18% sales decrease at constant exchange rates for Roche’s diagnostics division during the first three quarters of the year. This was more than enough to offset the 9% growth of its pharmaceuticals business. Roche’s best-selling pharma product is its multiple sclerosis therapy Ocrevus (ocrelizumab), which brought in more than $5.3 billion in the first nine months of 2023. This was followed by the hemophilia A treatment Hemlibra (emicizumab), breast cancer antibody Perjeta (pertuzumab) and blockbuster cancer immunotherapy Tecentriq (atezolizumab). Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Claudin 6 T Cell engagers: A novel strategy for solid tumorsAntibody immunotherapy has revolutionized oncology treatment for melanoma, lung, stomach, cervical, and certain types of breast cancer. While effective for many patients, current immunotherapy approaches are broad-acting, turning off or on entire populations of immune cells. This approach to systemic immune modulation can lead to debilitating autoimmune or bystander side effects for many patients. An alternative to non-selective immunotherapy is precision targeting which is intended to only activate immune cells within the tumor microenvironment and reduce the risk of systemic side effects. T cells are a type of white blood cell that play a central role in coordinating immune responses. One of their functions is to recognize and kill tumors, however tumor growth happens in part because the T cells dont effectively recognize the tumors. T cell engaging bispecific antibodies (TCE) are potent tumor-targeting agents that act by linking a patients T cells to proteins expressed on a cancer cell surface to create an augmented recognition that allows the T cells to kill the cancer cells. TCEs have had tremendous clinical success targeting blood cancers that express protein-based antigens including CD19, CD20, or B-cell maturation antigen (BCMA). However, TCE success in solid tumors has been limited, with only one treatment (Kimmtrak, tebentafusp) approved by the U.S. Food and Drug Administration to date. However, as researchers learn more about TCE and how best to use them, there is reason for optimism.Lessons learned and a path forwardDrug development is an iterative process and past failures for TCEs in solid tumors help guide product refinement for todays emerging TCE products. Compared to treating blood cancers, solid tumors require much higher doses of TCE to ensure enough T cells can enter the tumor microenvironment. However, increasing the peripheral exposure of the TCE in solid tumors heightens the risk of off-target toxicities. TCEs in solid tumors have historically been challenged by systemic spillover of the induced immune responses, including cytokine release syndrome (CRS), an acute systemic inflammatory syndrome that in extreme cases can lead to multi-organ failure. As the understanding of CRS has evolved, several critical risk factors have been identified that can be mitigated with improved target selection, TCE engineering, and by tailoring the pharmacokinetic profile of the TCE. The recent approval of Kimmtrak in uveal melanoma and promising early clinical data in small cell lung cancer programs targeting the DLL3 protein (AMG757, BI764532, HPN328) reflects this more refined understanding of TCE and unlocks the potential for TCE in solid tumor therapy.CRS tttRisk FactorCase StudiesMitigation StrategyTarget ExpressionEpCAM (AMG110), CEA (cibisatamab), PSMA (HPN424, AMG160), HER2 (Ertumaxomab, GBR1302), and SSTR2 (XmAb18087) experiencedttton-target/off-tumor toxicityTargets selectively expressed in cancer cells (CLDN6, DLL3) and/or increase target avidityADCC and CDC ActivityEpCAMxCD3 (HO-3) wildtype Fc with full effector functions resulted in significant toxicity in Phase 1Silence Fc or remove Fc domainAntidrug antibody (ADA) CEA (AMG211) and PSMA (MOR209) bispecifics induced aggregate formation and/or T cell scaffolding Target selection; fully humanized antibodyFast onset of actionCD20 (mosunetuzumab) and glypican 3 (ERY974) induced spikes in TCE concentration (Cmax)Utilize extended half-life TCE, lower/more frequent dose, or step-up dosing schemeFuture of TCE developmentThe early clinical success of TCE programs targeting DLL3 provides hope that other promising tumor antigens could achieve similar clinical outcomes. A critical determinant of this programs success may be that DLL3 expression is highly restricted to cancer cells. This minimizes off-tumor activation of T cells and the systemic toxicities that have been seen in some other TCE programs. Because other kinds of tumors will display different patterns of tumor antigens, identifying other cancer targets with similarly tumor-restricted patterns of expression is of significant interest to the cancer research community.One such emerging target of interest is Claudin 6 (CLDN6). CLDN6 is an embryonic gene that is turned on during fetal development and then silenced after birth, thus not expressed or expressed at low levels in normal healthy cells. Embryonic genes are often epigenetically reactivated by cancer cells as a survival mechanism to support the rapid growth of the tumor. Unlike DLL3, CLDN6 is enriched in a wide range of cancers, including non-small cell lung, testicular, and ovarian. Overall, it is estimated that there are 62,500 patients with metastatic CLDN6-positive cancer in the United States.The success of CLDN6-targeted TCE approaches will depend on the ability to optimize TCE engineering and dosing schedule to further minimize the risk of CRS. Two contrasting approaches are exemplified by CTIM-76 (Context Therapeutics) and AMG794 (Amgen). The Context and Amgen TCEs have both adopted FcRn-binding strategies to extend half-life and improve PK.Key to their success will be their ability to specifically target tumor-associated CLDN6 and the efficiency with which they can recruit T cells and their effector functions.CTIM-76AMG794Antibody FormatFull lengthFragmentFcR BindingReducedNoCD3 FormatMonovalent anti-CD3 scFvMonovalent anti-CD3 scFvDosingPotentially every 2-3 weeksWeeklyDefining the pathway to success for TCE in solid tumors has recently been solidified with a clear focus on optimization of TCE antibody engineering and TCE pharmacokinetics, and a selection of tumor-restricted targets. With these risk determinants in hand, TCEs are poised to have a significant impact on the treatment of solid tumors in the coming years. '