BLRX - Motixafortide Approval And Commercialization Likely In 2022 Based On Strong, Statistically Significant GENESIS Phase 3 Stem Cell Mobilization Data

Summary

• GENESIS Phase 3 demonstrated 92.5% of patients in the Motixafortide+G-CSF arm achieved the primary endpoint of mobilizing ≥6M CD34+ cells/kg in up to two apheresis sessions with a p<0.0001.
• This compares to only 26.2% for the placebo+G-CSF arm.
• GENESIS also showed 88.8% of patients in the Motixafortide+G-CSF arm achieved the secondary endpoint (mobilization of ≥6M CD34+ cells/kg in one apheresis session, p<0.0001), versus 9.5% for the placebo+G-CSF arm.
• 90% of the patients that received motixafortide in G-CSF underwent transplantation after only one administration compared to a similar study where 54% of patients were administered FDA approved Mozobil plus G-CSF.
• During the November 18, 2021 3Q financial and corporate update the company reported that it held $62.2M of cash, cash equivalents in short-term bank deposits as of September 30th, 2021. The company is well-financed to achieve multiple potentially value creating milestones.

Discussion

Several readers of my previous article on BLRX commented that it was too long. I have to agree with them, however, I believe that it is important to learn as much as you can about your investments in the stock market to maximize potential gains and minimize risks.

In this article, I will start with the conclusions so that potential investors can decide whether or not they want to keep reading it and how much to read.

Conclusions

• In May 2021, the company reported outstanding results from its GENESIS Phase 3 pivotal study in stem cell mobilization demonstrating that Motixafortide effectively mobilizes a high number of cells enabling ~90% of patients to undergo transplantation following a single administration of Motixafortide and a single apheresis session. In addition, the high number of cells mobilized by Motixafortide enables infusion of an optimal number of cells, which could result in faster time to engraftment, and also allows for cryopreservation for future transplantations. These results, together with the recently completed successful pharmacoeconomic study, strongly support our view that Motixafortide on top of G-CSF can become the new standard of care in SCM, if approved, to the benefit of patients and payers alike.
• In mid December 2021 at the 2021 ASH meeting Dr. Zachary Crees from the Washington University School of Medicine in St. Louis (WUSTL) noted that 92.5% of patients in the Motixafortide+G-CSF arm achieved the primary endpoint (the mobilization of ≥6M CD34+ cells/kg in up to two apheresis sessions, p<0.0001), versus 26.2% for the placebo+G-CSF arm. Furthermore, 88.8% of patients in the Motixafortide+G-CSF arm achieved the secondary endpoint (the mobilization of ≥6M CD34+ cells/kg in one apheresis session, p<0.0001), versus 9.5% for the placebo+G-CSF arm.
• In mid December, company management was expected to attend a pre-NDA meeting with the FDA. They hope to receive the formal minutes from the meeting by the first half of January.
• Assuming the pre-NDA meeting with the FDA is successful, management plans to submit an NDA to the FDA in the first half of 2022
• The company also plans to include evaluating lifecycle management potential in other autologous stem cell mobilization indications, for example, other lymphomas, sickle cell anemia, et cetera, as well as an allogeneic transplantation indications and neutropenia and others."
• CEO Serlin recently stated that they are actively engaged in productive discussions with potential commercialization partners for stem-cell mobilization. He commented: "The high level of interest we are receiving reflects the versatility of Motixafortide as the potential backbone of innovative new cancer treatments, something that we have demonstrated in two high-need indications so far."
• Importantly, 90% of the patients that received CXCR4 antagonist motixafortide in G-CSF underwent transplantation after only one administration compared to a similar study where 54% of patients were administered Genzyme's plerixafor/Mozobil plus G-CSF.
• Of note, Dr. Crees also indicated that 15–35% of patients still failed to yield optimal stem cell yields of ≥6M CD34+ cells/kg in two previously published plerixafor trials, even with up to four apheresis sessions. Additionally, Dr. Crees noted that advances in modern induction therapies for multiple myeloma patients have made the harvesting of a sufficient number of stem cells even more challenging, a trend that is expected to continue in the future, thus highlighting the need for new and improved mobilization therapies.
• Based on GENESIS data, motixafortide could eliminate the multiple apheresis procedures autologous stem cell transplant patients often need to undergo to allow enough cells to be collected. Five to six cycles is not uncommon, and sometimes the procedure fails for low cell yield. This is costly and an unnecessary burden for patients and their families.
• As a point of reference regarding valuation, Genzyme acquired plerixafor/Mozobil for $800M in 2021 dollars in 2016. This corresponds to over 6 times BiolineRx's current market cap.
• Regarding the use of motixafortide in pancreatic cancer, in December 2020 the company reported positive final results from the Phase 2a COMBAT/KEYNOTE-202 triple combination study of Motixafortide in combination with Merck’s anti PD-1 KEYTRUDA and chemotherapy as a second line therapy, a total of 43 patients initially diagnosed with unresectable stage four metastatic PDAC who had progressed following first-line gemcitabine based therapy were enrolled. Data from this study demonstrated the substantial improvement across all study endpoints as compared to historical data, including median overall survival, median progression free survival, confirmed overall response rate, overall response rate and disease control rate.
• Taken together the positive results that we have seen in trial to date across both stem cell mobilization and pancreatic cancer, reflect the underlying versatility of Motixafortide as the potential backbone of improved treatments for both hematological and solid tumor cancers.
• Motixafortide is also being studied in two notable investigator-initiated trials: in a Phase 2 study for the treatment of pancreatic cancer in combination with LIBTAYO® and chemotherapy, and in a Phase 1b study for patients with Acute Respiratory Distress Syndrome, or ADRS, secondary to COVID-19 and other respiratory viral infections.
• The investigator-sponsored study using motixafortide to treat ARDS on COVID-19 infected patients is interesting particularly since the virus variants don't seem to go away with the Delta variant causing global havoc and now a new Omicron variant being responsible for most infections in the US because of its higher transmissibility than other variants
• During the November 18, 2021 3Q financial and corporate update the company reported that it held $62.2M of cash, cash equivalents in short-term bank deposits as of September 30th, 2021. This provides the company with a runway through 2Q 2023.
• Currently two analysts rate BLRX as a BUY and have a $14.5/share average price target. Prolific Seekingalpha contributor believes that BiolineRx will be acquired in 2020 in the high-teens price area.
• I recommend that those interested in BLRX shares do a detailed review of the risks an uncertainties related to investing in this company as detailed in the company's filings with the SEC.

About BiolineRx

According to its website, BioLineRx Ltd. (NASDAQ:BLRX) is a late clinical-stage biopharmaceutical company focused on oncology. The Company's business model is to in-license novel compounds, develop them through clinical stages, and then partner with pharmaceutical companies for further clinical development and/or commercialization.

The company's lead program, motixafortide (BL-8040). Motixafortide is a novel highly selective and potent cyclic peptide CXCR4 inhibitor that has been proven effective in a variety of solid and liquid tumors. Motixafortide is a cancer therapy platform that was successfully evaluated in a Phase 3 study in stem cell mobilization for autologous bone-marrow transplantation, and has reported positive results from a pre-planned pharmacoeconomic study. These outstanding results support the goal of Motixafortide becoming the standard of care mobilization agent in autologous bone-marrow transplantation, and in this regard we are currently preparing an NDA submission.

Motixafortide was also successfully evaluated in a Phase 2a study for the treatment of pancreatic cancer in combination with KEYTRUDA® and chemotherapy under a collaboration agreement with MSD. Substantial improvement was observed across all study endpoints, including overall survival, progression free survival, and overall response rate, in the most challenging PDAC patients. The asset was also successfully evaluated in a Phase 2 study in r/r AML.

Motixafortide is also being studied in two notable investigator-initiated trials: in a Phase 2 study for the treatment of pancreatic cancer in combination with LIBTAYO® and chemotherapy, and in a Phase 1b study for patients with Acute Respiratory Distress Syndrome, or ADRS, secondary to COVID-19 and other respiratory viral infections.

BiolineRx's second oncology program, AGI-134, is a novel immunotherapy treatment for multiple solid tumors. This asset is currently being investigated in a Phase 1/2a study.

ASH 2021 Recap

On Dec. 17, 2021 BiolineRx (NASDAQ: BLRX) provided updates from an oral presentation delivered by Dr. Zachary Crees from the Washington University School of Medicine in St. Louis (WUSTL) at the 63^rd American Society of Hematology (ASH) Annual Meeting & Exposition, which was held December 11-14, 2021, in Atlanta, GA, and virtually.

The oral presentation, entitled, "Motixafortide (BL-8040) and G-CSF Versus Placebo and G-CSF to Mobilize Hematopoietic Stem Cells for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: The GENESIS Trial" elaborated on the successful results of the Company's GENESIS Phase 3 pivotal trial which assessed Motixafortide plus G-CSF for the mobilization of stem cells in multiple myeloma patients. The study showed highly significant and clinically meaningful results supporting the use of Motixafortide on top of G-CSF for mobilization of stem cells for subsequent collection and transplantation in patients with multiple myeloma.

Dr. Crees noted that 92.5% of patients in the Motixafortide+G-CSF arm achieved the primary endpoint (the mobilization of ≥6M CD34+ cells/kg in up to two apheresis sessions, p<0.0001), versus 26.2% for the placebo+G-CSF arm. Furthermore, 88.8% of patients in the Motixafortide+G-CSF arm achieved the secondary endpoint (the mobilization of ≥6M CD34+ cells/kg in one apheresis session, p<0.0001), versus 9.5% for the placebo+G-CSF arm.

Of note, Dr. Crees also indicated that 15–35% of patients still failed to yield optimal stem cell yields of ≥6M CD34+ cells/kg in two previously published plerixafor trials, even with up to four apheresis sessions. Additionally, Dr. Crees noted that advances in modern induction therapies for multiple myeloma patients have made the harvesting of a sufficient number of stem cells even more challenging, a trend that is expected to continue in the future, thus highlighting the need for new and improved mobilization therapies.

BilineRx CEO Philip Serlin commented:

"We were very pleased that Dr. Crees had an opportunity to deliver an oral presentation at ASH, one of the most prestigious and well attended oncology gatherings of the year, to provide additional details on the outstanding results from our GENESIS Phase 3 trial,"

"Along with the outstanding efficacy data from the trial and the positive results from the pharmacoeconomic study that we reported on previously, trends in the treatment paradigm, whereby new induction therapies in patients make the mobilization of stem cells ever more challenging, give us great enthusiasm for this molecule and emphasize its place as part of the standard of care in autologous stem cell transplantation. We look forward to a pre-NDA meeting with FDA in the coming days."

More on Motixafortide - A Potentially Blockbuster Multipurpose Drug

Motixafortide (formerly known as BL-8040/BKT140) is a novel selective inhibitor of the CXCR4 chemokine receptor. CXCR4, is a well validated therapeutic target that is involved in the mobilization and trafficking of hematopoetic stem cells, immune cells and cancer cells from the bone marrow and the lymph nodes to the peripheral blood.

Motixafortide’s unique features including high-affinity, long receptor occupancy and inverse agonist activity position it as the best-in-class antagonist of CXCR4 in development.

BiolineRx is currently developing motixafortide as a platform for several indications including mobilization of hematopoietic stem cells, treatment of solid tumors, and other hematological malignancies.

Motixafortide was successfully evaluated in a Phase 3 study in stem cell mobilization for autologous bone-marrow transplantation, and has reported positive results from a pre-planned pharmacoeconomic study. These outstanding results support the goal of Motixafortide becoming the standard of care mobilization agent in autologous bone-marrow transplantation, and in this regard we are currently preparing an NDA submission.

Motixafortide was also successfully evaluated in a Phase 2a study for the treatment of pancreatic cancer in combination with KEYTRUDA and chemotherapy under a collaboration agreement with MSD. Substantial improvement was observed across all study endpoints, including overall survival, progression-free survival, and overall response rate, in the most challenging PDAC patients.

Motixafortide was also successfully evaluated in a Phase 2 study in r/r AML and is currently being studied in two notable investigator-initiated trials: 1) in a Phase 2 study for the treatment of pancreatic cancer in combination with LIBTAYO® and chemotherapy; and 2) in a Phase 1b study for patients with Acute Respiratory Distress Syndrome (OTC:ARDS) Secondary to COVID-19 and other respiratory viral infections.

To understand how and why motixafortide works so effectively in solid and liquid cancer malignancies I think it is useful to understand or envision its mode of action (MOA). The graphic below shows how it frees up HSC or hematopoietic stem cells by blocking the binding tendency of CXC12 to CXCR4 so that they don't hide in their protective bone marrow niches. This causes HSCs to mobilize into the peripheral blood and that wat they can be collected by the process known as apheresis:

The following graphic depicts motixafortide's MOA in solid tumors. It overcomes limitation of immunotherapy drugs by acting as: 1) an immunomodulator by increasing the number of immune cells circulating on the periphery of tumor; 2) a potentiator that enables immune cells to enter the tumors so that can kill cancer cells; 3) a microtumor-environment modifier

CXCL12 is a homeostatic chemokine produced in multiple tissues including lymph nodes (LNs), brain, liver, colon, kidney, testis, lung, pancreas, skin and placenta, and in different cell types including stromal cells, osteoblasts, fibroblasts, dendritic cells and monocytes, among others. In simple words, fibroblastic cells at solid tumor edges produce CXCL12, which in turn work at isolating effector cells at the tumor edge similarly as a goalie in soccer works at preventing goals from being scored. Effector cells are are relatively short lived activated cells that defend the body in an immune response from cancer and other illnesses.

It has been reported that CXCL12 can be used for determining the location of metastasis in different tumors. Also, several studies point to CXCL12's potential as a biomarker in hepatocellular carcinoma, bladder cancer and glioma recurrence, and as a predictor of poor survival in ovarian cancer. CXCL12 also has prognosis potential in non-tumoral processes such as cirrhosis , diabetes, and cardiovascular diseases.

CXCR4, a validated chemokine receptor, is involved in numerous physiological and pathological conditions. CXCR4 is expressed by most cells, including hematopoietic and endothelial cells, neurons and stem cells (embryonic and adult). Increased levels of CXCR4 are present in cancer cells compared to the normal cells.

The CXCR4 chemokine receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application.

Motixafortide significantly suppress primary tumor growth and can prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages infiltration. Ultimately motixafortide promotes cytotoxic T cell infiltration into tumor as the illustrations above suggest.

It can be concluded that the therapeutic benefits of motixafortide can be extended to a myriad of types of liquid and solid cancers because of its strong ability to block CXCL12's interaction and binding onto chemokine receptor CXCR4. In short, the therapeutic possibilities with motixafortide seem to be endless and I believe that in the future with more resources and through partnerships it will be investigated in more indications with high unmet needs.

In summary, ongoing motixafortide studies include the following:

• Phase 3 double-blinded study for the combination treatment with BL-8040 (Motixafortide) and G-GSF (vs. placebo) for the mobilization of hematopoietic stem cells for autologous transplantation in subjects with multiple myeloma (GENESIS: NCT03246529)
• Phase 2a study of BL-8040 with Nelarabine for R/R T-Acute Lymphoblastic Leukemia / Lymphoblastic Lymphoma (NCT02763384)

• Phase 2 study of combination chemotherapy and motixafortide, and the immune checkpoint blockade - Cemiplimab for metastatic treatment of naive pancreas adenocarcinoma (NCT04543071)

• Phase 2 study of motixafortide for the mobilization of donor hematopoietic stem cells and allogeneic transplantation in subjects with advanced hematological malignancies (NCT02639559)

• Phase 1b open-label study of motixafortide for patients with acute respiratory distress syndrome secondary to COVID-19 and other respiratory viral infections

On November 18, 2020, BiolineRx announced that the Company's lead drug candidate, the CXCR4-inhibitor Motixafortide, will be evaluated in an investigator-initiated clinical trial in patients suffering from acute respiratory distress syndrome (OTC:ARDS) secondary to COVID-19 and other respiratory viral infections.

The primary endpoint of the study is to assess the safety of Motixafortide in patients with ARDS secondary to COVID-19 and other respiratory viral infections. Respiratory parameters and inflammatory biomarkers will be assessed as exploratory endpoints. Up to 25 patients will be enrolled, with a preliminary analysis planned after ten patients have completed the initial treatment period.

Brief Comparison of Motixafortide to FDA Approved CXCR4 Antagonists

The first CXCR4 antagonist to be FDA approved is plerixafor. It was originally developed to inhibit cell entry of HIV X4-strains via CXCR4; however, in vivo preclinical tests revealed a massive leukocytosis following plerixafor administration. This observation resulted in the launch of plerixafor (trade name Mozobil - Genzime) in 2008 as a first-in-class HSC mobilizing compound for the autologous transplantation of bone marrow (BM) cells in patients with Non-Hodgkin’s lymphoma and multiple myeloma.

Up to now, plerixafor has been tested in 165 clinical trials mainly with HSC recruitment for BM transplants as the primary clinical endpoint, but also for other indications such as Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, solid tumors, metabolic, cardiovascular, and pulmonary disorders.

However, plerixafor's application to solid tumors has been limited by its poor pharmacokinetics and toxic adverse effects after long-term administration according to some reports. Thus, a CXCR4 antagonist with higher safety and better pharmacological and pharmacokinetic profiles will likely have great potential to serve as a clinical agent for many unmet medical-need diseases targeting CXCR4 receptors.

An outcome of the pivotal motixafortide Phase 3 GENESIS clinical trials on stem cell mobilization was that approximately 90% of patients who received Motixafortide in G-CSF underwent transplantation after only one administration of Motixafortide. And then only one apheresis session, this compares to 10.8% for G-CSF alone.

As a comparison, while not a head to head study, GENESIS outstanding results compare very favorably to results from the registrational study of FDA approved plerixafor/MOZOBIL, which demonstrated that approximately 54% of patients went to transplantation after one administration of plerixafor on top of G-CSF and in one apheresis session.

OK.....so the clear bottom line is that 90% of the patients that received CXCR4 antagonist motixafortide in G-CSF underwent transplantation after only one administration compared to a similar study where 54% of patients were administered plerixafor/Mozobil plus G-CSF and 10.8% for G-CSF alone. Advantage motixafortide, right?....me thinks so.

One further advantage of using motixafortide, the large number of cells collected allows for the transplant of an optimal number of cells, as well as enabling the storage of a sufficient amount of remaining cells for future transplantation without the need for additional mobilization in apheresis procedures.

On October 2006, Genzyme Corporation and AnorMED Inc. announced an agreement under which Genzyme will acquire AnorMED in an all cash transaction valued at $13.50 per outstanding share, or approximately $580M (5 times BLRX market cap). The announcement stated: "Through this transaction, Genzyme is acquiring MOZOBIL, a leading late-stage product candidate in development for hematopoietic stem cell transplantation. MOZOBIL is being tested in Phase 3 clinical trials and is expected to launch in 2008".

On December 15, 2008 Mozobil was approved by the FDA for SCM.

Mozobil projected sales for 2021 are expected to be about $300M but without COVID-19 it is projected to surpass $500M in 2025.

The following slide is comparison to plerixafor/Mozobil showing clear motixafortide advantage:

Recap - GENESIS Phase 3 Results in Stem Cell Mobilization

On May 4, 2021, the company announced positive results from Phase 3 GENESIS trial - the company's most-advanced clinical study, evaluating Motixafortide (aka BL-8040), in combination with Granulocyte Colony Stimulating Factor ("G-CSF", the current standard care), for hematopoietic stem-cell mobilization ("SCM") for autologous bone marrow transplantation in multiple myeloma patients.

The study used 122 patients, out of which 42 were given the placebo. The below-mentioned ratios relate to the proportion of valid "treatment arms" compared to fake "placebo arms."

The primary endpoint of the study demonstrated a 4.9x increase (70.0% vs 14.3%), while showing a high level of statistical significance (p<0.0001) in mobilizing ≥ 6M CD34+ cells/kg in up to two aphereses, and after only a single dose of Motixafortide.

The study also achieved its main secondary endpoint, demonstrating a 14.1x increase (67.5% vs 4.8%), while showing a high level of statistical significance (p<0.0001) in mobilizing ≥ 6M CD34+ cells/kg in only one apheresis.

Other important data points include the following:

• a 5.6x increase (8.5M in the treatment arm vs 1.5M in the control arm) in the median number of CD34+ cells collected on the first day of apheresis.
• an 8.2x increase (88.3% vs 10.8%) in patients that had transplantation after only one apheresis session, with Motixafortide being added to G-CSF.

All in all, the combination (of Motixafortide plus G-CSF) was found to be safe and well tolerated, with the addition of Motixafortide making a real difference.

As mentioned above, not only has Motixafortide met and exceeded all targets, but it has proven itself to be a better treatment than a parallel-competing study using Plerixafor/Mozobil (a drug that was developed by AnorMED, which was taken over by Genzyme in 2008) for $580M in 2006 which adjusted for inflation becomes about $800M in 2021 dollars. This corresponds to over 6 times BiolineRx's market cap. This coincidentally equates to analysts' price target and TFT estimated acquisition price in 2022.

In connection to the discussion above, CEO Serlin stated the following during 3Q 2021 conference call held on August 18, 2021:

"First, the GENESIS study met all primary and secondary endpoints with an exceptionally high level of statistical significance, a P value of less than 0.0001. Perhaps most notably, approximately 90% of patients who received Motixafortide in G-CSF underwent transplantation after only one administration of Motixafortide. And then only one apheresis session, this compares to 10.8% for G-CSF alone."

"In addition, while not a head to head study, this compares very favorably to results from the registrational study of plerixafor, which demonstrated that approximately 54% of patients went to transplantation after one administration of plerixafor on top of G-CSF and in one apheresis session."

"Using the current standard-of-care with G-CSF alone, several apheresis sessions are generally required to collect the optimal number of stem-cells. However, somewhere between 30% and 50% of patients are unable to reach this optimal number of stem-cells. Due to the ability of Motixafortide in the vast majority of cases to enable the collection of an exceptionally high number of stem-cells following one administration with only one apheresis session, thereby lowering the number of G-CSF administrations apheresis sessions and related adverse events, we believe there's a compelling case to be made regarding the potentially significant clinical benefits as well as health system costs benefits that can be achieved with Motixafortide if approved."

"We also know that the higher number of cells collected allows for the transplant of an optimal number of cells, as well as enabling the storage of a sufficient amount of remaining cells for future transplantation without the need for additional mobilization in apheresis procedures."

"In this regard, we are running a pharmacoeconomic cost effectiveness study that we believe will demonstrate our case for the use of Motixafortide as the backbone for all new stem-cell mobilization procedures. This study is progressing as planned, and we look forward to reporting data by the end of this year (read update below):"

"In addition, we continue to perform additional analyses that were predefined in the statistical analysis plan, as well as post-hoc analysis of the GENESIS data set and look forward to presenting our additional findings from the study at future medical meetings (ASH 2021)."

"As previously mentioned, this program represents our fastest track to registration. And to that end, we are aggressively working on activities in support of a U.S. new drug application or NDA, which we plan to submit in first half of next year. We are making preparations now for a pre-NDA meeting with the agency that we anticipate will occur prior to the end of this year."

"If ultimately approved in this indication, we would begin our transition to accompany with a commercial stage molecule, the most important and transformational milestone that we will have achieved as a company to this point. We would have a commercial stage molecule in one indication with significant potential utility in other cancer types as well, most notably pancreatic cancer, which we will discuss next."

"In addition, based on the strength of the GENESIS results, we are also exploring development of Motixafortide and other stem-cell mobilization indications as part of its lifecycle management program."

Regarding the pharmaeconomic analysis that CEO Serlin promised for 4Q 2021, these results were published on October 13, 2021 "BioLineRx Announces Positive Results from Pharmacoeconomic Study Positioning Motixafortide as Potential Standard of Care in Stem Cell Mobilization."

During the November 18, 2021 3Q 2-21 conference call, CEO Philip Serlin commented:

"Now turning to the pharmacoeconomic analysis. First, a little background to help in better understanding the results and significant clinical benefits.:

"Autologous stem cell transplantation is part of the standard treatment paradigm for a number of blood cancers, including multiple myeloma, non-Hodgkin's lymphoma and other lymphomas. In eligible patients, autologous transplantations report is performed after initial induction therapy. And in most cases requires consecutive day clinic visits for the mobilization in the aphoresis or harvesting phases. It also generally requires costly inpatient hospitalization for the conditioning chemotherapy and transplantation phases until engraftment, a process that typically takes two to four weeks."

"The associated burden is therefore significant. Patients experience clinically relevant deteriorations in their quality of life during autologous transplantation and healthcare resource use throughout the autologous transplantation phases is particularly intense. Therefore, new interventions impacting the autologous transplantation process have the potential to relieve some of the clinical and the logistical burdens for transplanted patients. The logistical burden for the aphoresis units and the financial burden for healthcare providers and payers."

"Described simply, autologous transplantation consists of, first, mobilizing the patient's own stem cells from his or her bone marrow to the peripheral blood for removing or harvesting via an aphoresis procedure. Second, freezing and storing the harvest itself until they are needed for transplantation. Third, providing a conditioning treatment such as high dose chemotherapy or radiation to kill the remaining cancer cells the day before transplant; and finally, infusing the stored stem cells back to the patient intravenously via a catheter."

"To mobilize the patient's stem cells from the bone marrow to the peripheral blood for harvesting, the current standard-of-care includes the administration of five to eight daily doses of G-CSF and the performance of one to four aphoresis sessions. For patients unable to mobilize sufficient numbers of cells for harvesting during this primary mobilization phase rescue therapy is carried out, consisting of one to four doses of plerixafor on top of G-CSF. And the performance of an additional number of aphoresis sessions is necessary."

"In light of this, an agent with superior mobilization activity like Motixafortide may significantly reduce the mobilization and harvesting burden and associated risks of the autologous transplantation process and lead to significant clinical and resource benefits. And it is this hypothesis that was tested in the pharmacoeconomic study. The study was performed by the global Health Economics and Outcomes Research, the HEOR team of IQVIA, one of the leading global data and technology firms focusing on the healthcare sector."

"The pharmacoeconomic study analyze healthcare resource utilization observed during the GENESIS trial in each of the two randomized arms, Motixafortide in combination with G-CSF with a patient number of 80 or placebo in combination with G-CSF with the patient number of 42. Health Resource Use, known as HRU, data points collected, included the number of Motixafortide in G-CSF doses, as well as the number of aphoresis sessions performed in the primary mobilization phase, the percentage of patients needing rescue mobilization due to poor primary mobilization, including the number of aphoresis sessions needed and the number of G-CSF and plerixafor doses required.:"

"And three, hospitalization costs related to conditioning and transplantation, including length of stay. Quality adjusted life years gained from published literature were also incorporated into the model. Motixafortide plus G-CSF was associated with a statistically significant HRU decreased during the autologous stem cell transplantation process compared to standard-of-care G-CSF alone."

"Given the higher number of mobilized cells and the lower number of aphoresis sessions, lifetime estimates showed quality adjusted life year benefits and net cost savings of approximately $17,000 not including the cost of Motixafortide versus the current standard-of-care."

"We believe that the compelling cost savings identified by this rigorously designed study strongly support our view that Motixafortide in combination with G-CSF can become the new standard-of-care as an upfront or primary therapy for all multiple myeloma patients undergoing autologous M stem cell transplantation."

The bottom line regarding motixafortide's performance mobilizing stem cells compared to SCM is summarized on the following slide:

John DiPersio, MD, Washington University School of Medicine said this recently:

“The results of the GENESIS study are extremely impressive, and all the more so when considering that almost 90% of the patients in the treatment arm proceeded to transplantation after only 1 apheresis session. This is a great achievement in alleviating the burden for the patients and reducing hospital resources. I believe these results make the combination of motixafortide and G-CSF a very attractive candidate for use in all patients with multiple myeloma undergoing autologous stem-cell transplantation.”

Motixafortide in Metastatic Pancreatic Cancer

The second high-need indication CEO Serlin mentioned above is the ongoing Phase 2a COMBAT/KEYNOTE-202, assessing the safety and efficacy of motixafortide in combination with KEYTRUDA and chemotherapy in patients with stage IV metastatic pancreatic cancer, who had progressed following first-line treatment with gemcitabine-based chemotherapy with gemcitabine-based chemotherapy.

On December 16, 2020, the company reported preliminary data from the triple combination arm of the ongoing Phase 2a COMBAT/KEYNOTE-202. At that time, of the 40 patients to be enrolled in the study, 36 had been enrolled, while 30 patients were evaluable for safety and 22 for efficacy.

Best response for the evaluable population of 22 patients showed 7 partial response (PR) and 10 stable disease patients, resulting in an overall response rate (ORR) of 32% and a disease control rate (DCR) of 77%, which compares favorably to the current chemotherapy standard-of-care treatment in second-line patients with ORR of 17% and DCR of 52%.

The combination showed a lasting effect: 5 patients with stable disease became partial responders as treatment continued; out of the 7 partial responders, 5 were still on treatment, with a current maximum treatment time of 330+ days; and 4 responders showed a reduction in tumor burden of >50%; median duration of clinical benefit until progression for the 17 patients with disease control (7 PR and 10 SD patients) is 7.8 months.

The combination was generally well tolerated, with a safety profile consistent with the individual safety profile of each component.

Commenting on these results, CEO Serlin stated the following during the 3Q 2021 conference call:

"Recall that in December we announced positive final results from the Phase 2a COMBAT/KEYNOTE-202 triple combination study of Motixafortide in combination with Merck’s anti PD-1 KEYTRUDA and chemotherapy as a second line therapy, a total of 43 patients initially diagnosed with unresectable stage four metastatic PDAC who had progressed following first-line gemcitabine based therapy were enrolled. Data from this study demonstrated the substantial improvement across all study endpoints as compared to historical data, including median overall survival, median progression free survival, confirmed overall response rate, overall response rate and disease control rate."

"With regard to next steps for our PDAC program, as we previously indicated, we continue to engage in discussions with potential biopharma partners, with the goal of collaborating on a randomized controlled Phase 2/3 study."

"Taken together the positive results that we have seen in trial to date across both stem cell mobilization and PDAC, reflect the underlying versatility of Motixafortide as the potential backbone of improved treatments for both hematological and solid tumor cancers. We have an opportunity to highlight this fact that this year's American Society of Hematology Annual Meeting & Exposition or ASH, which is taking place December 11th to December 14."

BiolineRx Second Oncology Candidate Solid Tumor Vaccine AGI-134

The company announced on March 23, 2017, the acquisition of UK-based private oncology company Agalimmune for $6M in cash and stock. Agalimmune's lead drug candidate was AGI-134.

AGI-134 is a synthetic alpha-Gal glycolipid immunotherapy in development for solid tumours that harnesses the body’s pre-existing, highly abundant, anti-alpha-Gal antibodies to induce a hyper-acute, systemic, specific anti-tumour response to the patient’s own tumour neo-antigens. This response not only kills the tumour cells at the site of injection, but also brings about a durable, follow-on immune response, triggering a vaccine effect possibly preventing the development of future metastases.

AGI-134 works by harnessing the body's own immune system to kill solid tumors. The drug is injected into a target tumor, and through a series of events, it kills the local tumor. Once debris from the killed tumor enters the blood stream, the body's immune system generates and programs T-cells, based on the chemical structure of the killed tumor, and attacks and kills all the other tumors that resulted through metastasis. This results in a personalized treatment, potentially leading to improved responses over other existing solid-tumor technologies.

AGI-134 has a strong potential as a novel immunotherapy for solid tumors. The unique mechanism of action of AGI-134 addresses directly two key issues in cancer therapy. The first is inter and intra-patient tumor neoantigen heterogeneity. The second is the non-inflammatory, or cold, tumor microenvironment, that limits responsiveness to existing immunotherapies.

In preclinical studies, AGI-134 demonstrated effective destruction of secondary tumors and provided robust protection against the formation of new tumors in a model of melanoma with a single dose only. The drug has also demonstrated a synergistic effect when combined with checkpoint inhibitors in additional pre-clinical studies. This is another reason BLRX's management is so bullish about the drug's prospects since it would offer the opportunity to improve the rate and duration of responses in multiple cancer types by working in conjunction with checkpoint inhibitors.

The slide below shows the conceptual AGI-134 MOA - Source: October 2021 Corporate Presentation:

Fast-forward to today AGI-134 is currently evaluated in a Phase 1/2a study in solid tumours.

In the November 18, 2021 3Q 2021 conference call CEO Serlin updated the status of this promising drug candidate as follows:

"Regarding our second clinical candidate, AGI-134, recall that we are evaluating safety, tolerability and proof of mechanism in multiple solid tumor types in a Phase 1/2a study. The study is designed to evaluate a wide array of biomarkers and assessable clinical and pharmacodynamic parameters.

"In September, 2019, we announced positive safety data. And later that same month, we moved quickly to initiate Part 2 to dose expansion phase. As we have discussed, the COVID-19 pandemic did impact enrollment for a period of time, but it's now resumed. At this stage, it looks like we will complete recruitment by the end of this year and be in a position to announce results from the trial in the first half of next year. "

Pipeline

Investment Highlights

Before I start my analysis on BiolineRX, I would like to share the following slide that I've extracted from the company's October 2021 Corporate Presentation:

Upcoming Milestones

Source: October 2021 Corporate Presentation:

Financial Situation

During the November 18, 2021 3Q financial and corporate update the company reported that it held $62.2M of cash, cash equivalents in short-term bank deposits as of September 30th, 2021. CFO Mali Zeevi We commented "We believe we are well-financed to achieve multiple potentially value creating milestones."

Analyst Opinion

Currently two analysts rate BLRX as a BUY and have a $14.5/share average price target

Conclusions

• In May 2021, the company reported outstanding results from its GENESIS Phase 3 pivotal study in stem cell mobilization demonstrating that Motixafortide effectively mobilizes a high number of cells enabling ~90% of patients to undergo transplantation following a single administration of Motixafortide and a single apheresis session. In addition, the high number of cells mobilized by Motixafortide enables infusion of an optimal number of cells, which could result in faster time to engraftment, and also allows for cryopreservation for future transplantations. These results, together with the recently completed successful pharmacoeconomic study, strongly support our view that Motixafortide on top of G-CSF can become the new standard of care in SCM, if approved, to the benefit of patients and payers alike.
• In mid December 2021 at the 2021 ASH meeting Dr. Zachary Crees from the Washington University School of Medicine in St. Louis (WUSTL) noted that 92.5% of patients in the Motixafortide+G-CSF arm achieved the primary endpoint (the mobilization of ≥6M CD34+ cells/kg in up to two apheresis sessions, p<0.0001), versus 26.2% for the placebo+G-CSF arm. Furthermore, 88.8% of patients in the Motixafortide+G-CSF arm achieved the secondary endpoint (the mobilization of ≥6M CD34+ cells/kg in one apheresis session, p<0.0001), versus 9.5% for the placebo+G-CSF arm.
• In mid December, company management was expected to attend a pre-NDA meeting with the FDA. They hope to receive the formal minutes from the meeting by the first half of January.
• Assuming the pre-NDA meeting with the FDA is successful, management plans to submit an NDA to the FDA in the first half of 2022
• The company also plans to include evaluating lifecycle management potential in other autologous stem cell mobilization indications, for example, other lymphomas, sickle cell anemia, et cetera, as well as an allogeneic transplantation indications and neutropenia and others."
• CEO Serlin recently stated that they are actively engaged in productive discussions with potential commercialization partners for stem-cell mobilization. He commented: "The high level of interest we are receiving reflects the versatility of Motixafortide as the potential backbone of innovative new cancer treatments, something that we have demonstrated in two high-need indications so far."
• Importantly, 90% of the patients that received CXCR4 antagonist motixafortide in G-CSF underwent transplantation after only one administration compared to a similar study where 54% of patients were administered Genzyme's plerixafor/Mozobil plus G-CSF.
• Of note, Dr. Crees also indicated that 15–35% of patients still failed to yield optimal stem cell yields of ≥6M CD34+ cells/kg in two previously published plerixafor trials, even with up to four apheresis sessions. Additionally, Dr. Crees noted that advances in modern induction therapies for multiple myeloma patients have made the harvesting of a sufficient number of stem cells even more challenging, a trend that is expected to continue in the future, thus highlighting the need for new and improved mobilization therapies.
• Based on GENESIS data, motixafortide could eliminate the multiple apheresis procedures autologous stem cell transplant patients often need to undergo to allow enough cells to be collected. Five to six cycles is not uncommon, and sometimes the procedure fails for low cell yield. This is costly and an unnecessary burden for patients and their families.
• As a point of reference regarding valuation, Genzyme acquired plerixafor/Mozobil for $800M in 2021 dollars in 2016. This corresponds to over 6 times BiolineRx's current market cap.
• Regarding the use of motixafortide in pancreatic cancer, in December 2020 the company reported positive final results from the Phase 2a COMBAT/KEYNOTE-202 triple combination study of Motixafortide in combination with Merck’s anti PD-1 KEYTRUDA and chemotherapy as a second line therapy, a total of 43 patients initially diagnosed with unresectable stage four metastatic PDAC who had progressed following first-line gemcitabine based therapy were enrolled. Data from this study demonstrated the substantial improvement across all study endpoints as compared to historical data, including median overall survival, median progression free survival, confirmed overall response rate, overall response rate and disease control rate.
• Taken together the positive results that we have seen in trial to date across both stem cell mobilization and pancreatic cancer, reflect the underlying versatility of Motixafortide as the potential backbone of improved treatments for both hematological and solid tumor cancers.
• Motixafortide is also being studied in two notable investigator-initiated trials: in a Phase 2 study for the treatment of pancreatic cancer in combination with LIBTAYO® and chemotherapy, and in a Phase 1b study for patients with Acute Respiratory Distress Syndrome, or ADRS, secondary to COVID-19 and other respiratory viral infections.
• The investigator-sponsored study using motixafortide to treat ARDS on COVID-19 infected patients is interesting particularly since the virus variants don't seem to go away with the Delta variant causing global havoc and now a new Omicron variant being responsible for most infections in the US because of its higher transmissibility than other variants
• During the November 18, 2021 3Q financial and corporate update the company reported that it held $62.2M of cash, cash equivalents in short-term bank deposits as of September 30th, 2021. This provides the company with a runway through 2Q 2023.
• Currently two analysts rate BLRX as a BUY and have a $14.5/share average price target. Prolific Seekingalpha contributor believes that BiolineRx will be acquired in 2020 in the high-teens price area.
• I recommend that those interested in BLRX shares do a detailed review of the risks an uncertainties related to investing in this company as detailed in the company's filings with the SEC.