People often complain about how long it can take to turn a scientific discovery into an approved therapy for patients. And they’re right. It can take years, decades even. But for Immune-Onc Therapeutics the path to FDA approval may just have been shortened.
Back in April of 2021 the California Institute for Regenerative Medicine (CIRM) approved investing $6 million in Immune-Onc to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). AML and CMML are both types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.
Dr. Paul Woodard and his team are treating patients with an antibody therapy called IO-202 that targets leukemic stem cells. The antibody works by blocking a signal named LILRB4 which is associated with decreased rates of survival in AML patients. The goal is to attain complete cancer remissions and prolonged survival.
Well, they must be doing something right because they just received Fast Track designation from the US Food and Drug Administration (FDA) for IO-202. Getting this designation is a big deal because its goal is to speed up the development and review of drugs to treat serious conditions and fill an unmet medical need to get important new medicines to patients earlier.
Getting a Fast Track designation means the team at Immune-Onc may be:
Eligible for more written communications and even face-to-face meetings with the FDA to discuss the development plan of IO-202
Eligible for Accelerated Approval and Priority Review if relevant criteria are met, which may result in faster approval.
In a press release Dr. Woodard said this was great news. “We are pleased that the FDA has granted IO-202 Fast Track designation in recognition of its potential to improve outcomes for people with relapsed or refractory AML. We look forward to working closely with the FDA to accelerate the clinical development of IO-202, which is currently being evaluated as a monotherapy and in combination with other agents in a Phase 1 dose escalation and expansion trial in patients with AML with monocytic differentiation and in chronic myelomonocytic leukemia (CMML).”
The FDA also granted IO-202 Orphan Drug Designation for treatment of AML in 2020. That’s defined as a therapy that’s intended for the treatment, prevention or diagnosis of a rare disease or condition, affecting less than 200,000 persons in the US.
Getting Orphan Drug Designation qualifies Immune-Onc for incentives including tax credits for clinical trials and the potential for seven years of market exclusivity if and when it is fully approved by the FDA.
When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.
The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.
The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.
Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.
Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.
CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.
Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.
It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.
Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $14.4 million for two new clinical trials for blood cancer and pediatric brain tumors.
These awards bring the total number of CIRM-funded clinical trials to 70.
$6.0 million was awarded to Immune-Onc Therapeutics to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), both of which are types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.
Paul Woodard, M.D. and his team will treat AML and CMML patients with an antibody therapy called IO-202 that targets leukemic stem cells. The antibody works by blocking a signal named LILRB4 whose expression is connected with decreased rates of survival in AML patients. The goal is to attain complete cancer remissions and prolonged survival.
$8.4 million was also awarded to City of Hope to conduct a clinical trial for children with malignant brain tumors. Brain tumors are the most common solid tumor of childhood, with roughly 5,000 new diagnoses per year in the United States.
Leo D. Wang, M.D., Ph.D. and his team will treat pediatric patients with aggressive brain tumors using chimeric antigen receptor (CAR) T cell therapy. The CAR T therapy involves obtaining a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them so that they are able to identify and destroy the brain tumors. The aim of this approach is to improve patient outcome.
“Funding the most promising therapies for aggressive blood cancer and brain tumors has always aligned with CIRM’s mission,” says Maria T. Millan, M.D., President and CEO of CIRM. “We are excited to fund these trials as the first of many near-term and future stem cell- and regenerative medicine-based approaches that CIRM will be able to support with bond funds under Proposition 14”.
An antibody therapeutic, magrolimab, being tested for myelodysplastic syndrome (MDS), a group of cancers in which the bone marrow does not produce enough healthy blood cells , was granted breakthrough therapy designation with the Food and Drug Administration (FDA).
Breakthrough therapy designations from the FDA are intended to help expedite the development of new treatments. They require preliminary clinical evidence that demonstrates that the treatment may have substantial improvement in comparison to therapy options currently available. CIRM funded a Phase 1b trial in MDS and acute myeloid leukemia (AML), another type of blood cancer, that provided the data on which the breakthrough therapy designation is based.
Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.
Magrolimab was initially developed by a team led by Irv Weissman, M.D. at Stanford University with the support of CIRM awards. This led to the formation of Forty Seven, Inc., which was subsequently acquired by Gilead Sciences in April 2020 for $4.9 billion (learn more about other highlighted partnership events on CIRM’s Industry Alliance Program website by clicking here).
In CIRM’s 2019-2020 18-Month Report, Mark Chao, M.D., Ph.D., who co-founded Forty Seven, Inc. and currently serves as the VP of oncology clinical research at Gilead Sciences, credits CIRM with helping progress this treatment.
“CIRM’s support has been instrumental to our ability to rapidly progress Forty Seven’s CD47 antibody targeting approach.”
Magrolimab is currently being studied as a combination therapy with azacitidine, a chemotherapy drug, in a Phase 3 clinical trial in previously untreated higher risk MDS. This is one of the last steps before seeking FDA approval for widespread commercial use.
In a press release, Merdad Parsey, M.D., Ph.D., Chief Medical Officer at Gilead Sciences discusses the significance of the designation from the FDA and the importance of the treatment.
“The Breakthrough Therapy designation recognizes the potential for magrolimab to help address a significant unmet medical need for people with MDS and underscores the transformative potential of Gilead’s immuno-oncology therapies in development.”
While doctors are still trying to better understand how to treat some of the most severe cases of COVID-19, researchers are looking at their current scientific “toolkit” to see if any potential therapies for other diseases could also help treat patients with COVID-19. One example of this is a treatment developed by Fate Therapeutics called FT516, which received support in its early stages from a Late Stage Preclinical grant awarded by CIRM.
FT516 uses induced pluripotent stem cells (iPSCs), which are a kind of stem cell made from reprogrammed skin or blood cells. These newly made stem cells have the potential to become any kind of cell in the body. For FT516, iPSCs are transformed into natural killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system and play a role in fighting off viral infections.
Prior to the coronavirus pandemic, FT516 was used in a clinical trial to treat patients with acute myeloid leukemia (AML) and B-cell lymphoma, which are two different kinds of blood cancer.
Due to the natural ability of NK cells to fight off viruses, it is believed that FT516 may also help play a role in diminishing viral replication of the novel coronavirus in COVID-19 patients. In fact, Fate Therapeutics, in partnership with the University of Minnesota, has treated their first COVID-19 patient with FT516 in a new clinical trial.
In a news release, Dr. Joshua Rhein, Physician at the University of Minnesota running the trial site, elaborates on how FT516 could help COVID-19 patients.
“The medical research community has been mobilized to meet the unique challenges that COVID-19 presents. There are limited treatment options for COVID-19, and we have been inundated daily with reports of varying quality describing the potential of numerous therapies. We know that NK cells play an important role in responding to SARS-CoV-2, the virus responsible for COVID-19, and that these cells often become depleted in infected patients. Our intent is to replenish NK cells in order to restore a functional immune system and directly target the virus.”
In its own response to the coronavirus pandemic, CIRM has funded three clinical trials as part of $5 million in emergency funding for COVID-19 related projects. They include the following: a convalescent plasma study conducted by Dr. John Zaia at City of Hope, a treatment for acute respiratory distress syndrome (a serious and lethal consequence of COVID-19) conducted by Dr. Michael Matthay at UCSF, and a study that also uses NK cells to treat COVID-19 patients conducted by Dr. Xiaokui Zhang at Celularity Inc. Visit our dashboard page to learn more about these clinical projects.
One of the hottest areas in cancer research right now is the use of CAR-T treatments. These use the patient’s own re-engineered immune system cells to target and kill the tumor. But the thing that makes it so appealing – using the patient’s own cells – also makes it really complicated and expensive. Creating a custom-made therapy from each patient’s own cells takes time and costs a lot of money. But now a new approach could change that.
Fate Therapeutics has developed an off-the-shelf therapy (thanks to CIRM funding) that could, theoretically, be stored at hospitals and clinics around the country and used whenever it’s needed for anyone who needs it.
Equally impressive is that 42 days after being treated with FT516, the man showed no signs of leukemia in either his bone marrow or blood.
FT516 is designed to provide a one-two combination attack on cancer. It’s made up of the wonderfully named natural killer (NK) cells, which are a critical part of our immune system defenses against cancer. These NK cells are created by using the iPSC process and have been genetically modified to express a protein that boosts their cancer-killing abilities.
Because these cells are manufactured they can, if effective, be produced in large numbers and stored for whenever needed. That would not only dramatically reduce costs but also make them more widely available when they are needed.
This is only one patient and the follow-up is still relatively short. Even so, the results are encouraging and certainly give hope that Fate is on to something big. We’ll be keeping track and let you know how things progress.
With more than 17,000 members from nearly 100 countries, the American Society of Hematology (ASH) is an organization composed of clinicians and scientists around the world working to conquer various blood diseases. Currently, they are having their 61st Annual ASH Meeting to highlight some of the exciting work going on in the field. Four of our CIRM funded trials have released promising results at this conference and we wanted to take the opportunity to highlight them below.
Sangamo Therapeutics is conducting a CIRM-funded clinical trial for beta-thalassemia, a severe form of anemia caused by mutations in the hemoglobin gene. The therapy Sangamo is testing takes a patient’s own blood stem cells and, using a gene-editing technology called zinc finger nuclease (ZFN), provides a functional copy of the hemoglobin gene. These modified cells are then given back to the patient. The company announced preliminary results from their first three patients treated. in the clinical trials at the ASH 2019 Conference as well.
Some of the highlights are the following:
The first three patients experienced prompt hematopoietic reconstitution, meaning that their supply of blood stem cells was restored.
The first three patients experienced no clonal hematopoiesis, meaning that the blood stem cells did not create cells with mutations in the DNA
Additional study results are expected in late 2020 once enrollment is complete and all six patients have longer follow-up
You can read more detailed results regarding the first three patients in the press release.
Forty Seven, Inc.
In another CIRM funded trial, Forty Seven, Inc. is testing a treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The treatment involves an antibody called magrolimab in combination with the chemotherapy drug azacitidine. Cancer cells express a signal that send a “don’t eat me” message to white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect these evasive cancer cells. The goal is to use both magrolimab and azacitidine to make the cancer stem cells vulnerable to being attacked and destroyed by the immune system.
Of the 46 patients evaluated, 24 patients had untreated higher-risk MDS and 22 patients had untreated AML. None of the patients were eligible for treatment with chemotherapy.
In higher-risk MDS, the overall response rate (ORR), which is the proportion of patients in a trial whose tumor is destroyed or significantly reduced by a treatment, was 92%.
Within this group of patients with an ORR, the following was observed:
12 patients (50%) achieved a complete response (CR), meaning that they experienced a disappearance of all signs of cancer in response to treatment.
Two patients (8%) achieved hematologic (blood) improvement.
Additionally, two patients (8%) achieved stable disease, meaning the cancer is neither increasing nor decreasing in extent or severity.
In untreated AML, the ORR was 64% and the following was observed within this group patients with an ORR:
Nine patients (41%) achieved a CR
Three patients (14%) achieved a CR with an incomplete blood count recovery (CRi)
One patient (5%) achieved a morphologic leukemia-free state (MLFS), which is defined as the disappearance of all cells with morphologic characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
Seven patients (32%) achieved stable disease (SD)
The median time to response among MDS and AML patients treated with the combination was 1.9 months.
More details regarding these results are available via the news release.
Onceternal Therapeutics, which is conducting a CIRM-funded trial for a treatment for lymphoma and leukemia, presented results at the 2019 ASH Meeting. The treatment involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs.
Some of the results presented are summarized as follows:
Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR.
Five patients had stable disease.
The total clinical benefit rate was 100%.
None of the patients died or saw their disease progress.
Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on the combination therapy.
The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib by itself was blunted with the addition of cirmtuzumab, and leukemic cell counts returned toward baseline and normal levels rapidly.
Last, but not least, Rocket Pharmaceuticals presented results at the 2019 ASH Conference related to a CIRM-funded trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare pediatric disease caused by a mutation in a specific gene that affects the body’s ability to combat infections. As a result, there is low expression of neutrophil (CD18). The company is testing a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.
Here are some of the highlights from the presentation:
Initial results from the first pediatric patient treated demonstrate early evidence of safety and potential effectiveness.
The patient exhibited early signs of engraftment
The patient also displayed visible improvement of multiple disease-related skin lesions after receiving therapy
No safety issues related to administration have been identified
More detailed results on this trial are available via the news release.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both types of blood cancers that can be difficult to treat. CIRM is fundingForty Seven, Inc. to conduct a clinical trial to treat patients with these blood cancers with an antibody called 5F9. CIRM has also given multiple awards prior to the clinical trial to help in developing the antibody.
Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, which are white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. The antibody works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.
In a press release, Forty Seven, Inc. announced early clinical results from their CIRM funded trial using the antibody to treat patients with AML and MDS. Some patients received just the antibody while others received the antibody in combination with azacitidine, a chemotherapy drug used to treat these cancers.
Here is a synopsis of the trial:
35 patients treated in a Phase 1 clinical trial have been evaluated for a response assessment to-date.
10 of these have MDS or AML and only received the 5F9 antibody.
11 of these have higher-risk MDS and received the 5F9 antibody along with the chemotherapy drug azacitidine.
14 of these have untreated AML and received the 5F9 antibody along with the chemotherapy drug azacitidine.
For the 11 patients with higher-risk MDS treated with the antibody and chemotherapy, they found that:
All 11 patients achieved an objective response rate (ORR),meaning that there was a reduction in tumor burden of a predefined amount.
Six of these patients achieved a complete response (CR), indicatinga disappearance of all signs of cancer in response to treatment.
For the 14 patients with untreated AML treated with the antibody and chemotherapy, they found that:
Nine of these patients achieved an ORR.
Five of theseninepatients achieved a CR.
Two of these nine patientsachieved a morphologic leukemia-free state (MLFS), indicating the disappearance of all cells with formal and structural characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
The remaining five patients achieved stable disease (SD), meaning that the tumor is neither growing nor shrinking.
The results also showed that:
There was no evidence of increased toxicities when the antibody was used alongside the chemotherapy drugs, demonstrating tolerance and safety of the treatment.
No responding MDS or AML patient has relapsed or progressed on the antibody in combination with chemotherapy, with a median follow-up of 3.8 months.
The median time to response was rapid at 1.9 months.
Several patients have experienced deepening responses over time resulting in complete remissions.
Based on the favorable results observed in this clinical trial to-date, expansion cohorts have been initiated, meaning that additional patients will be enrolled in a phase I trial. This will include patients with both higher-risk MDS and untreated AML as well as using the antibody in combination with chemotherapy.
In the press release, Dr. David Sallman, an investigator in the clinical trial, is quoted as saying,
“These new data for 5F9 show encouraging clinical activity in a broad population of patients with MDS and AML, who may be unfit for existing therapeutic options or at higher-risk for developing rapidly-advancing disease. Despite an evolving treatment landscape, physicians continue to seek new therapies for MDS and AML that can be used safely in combination with standard-of-care to help patients more rapidly achieve durable responses. To that end, I am excited to see meaningful clinical activity in a majority of patients treated with 5F9 in combination with azacitidine, with a median time to response of under two months and no relapses or progressions among responding patients.”
The “Valley of Death” sounds like a scary place from “Lord of the Rings” or “Game of Thrones” that our heroes have to navigate to reach safety. The reality is not that different. It’s the space that young companies have to navigate from having a good idea to getting financial backing, so they can move their projects towards the clinic. At the other side of the Valley are deep-pocket investors, waiting to see what makes it through before deciding if they want to support them.
It’s a Catch 22 situation. Without financing companies can’t make it through the Valley; but they need to get through before the folks with money will considering investing. As a result many companies languish or even fail to make it through the Valley of Death. Without that financial support promising therapies are lost before they even get a chance to show their potential.
CIRM was created, in part, to help those great ideas get through the Valley. That’s why it is so gratifying to hear the news today from ViaCyte – that is developing a promising approach to treating type 1 diabetes – that they have secured $80 million in additional financing.
The money comes from Bain Capital Life Sciences, TPG and RA Capital Management and several other investors. It’s important because it is a kind of vote of confidence in ViaCyte, suggesting these deep-pocket investors believe the company’s approach has real potential.
In a news release Adam Koppel, a Managing Director at Bain, said:
“ViaCyte is the clear leader in beta cell replacement, and we are excited about the lasting impact that it’s stem cell-derived therapies can potentially have on improving treatment and quality of life for people living with insulin-requiring diabetes. We look forward to partnering with ViaCyte’s management team to accelerate the development of ViaCyte’s transformative cell therapies to help patients.”
CIRM has been a big supporter of ViaCyte for several years, investing more than $70 million to help them develop a cell therapy that can be implanted under the skin that is capable of delivering insulin to people with type 1 diabetes when needed. The fact that these investors are now stepping up to help it progress suggests we are not alone in thinking this project has tremendous promise.
But ViaCyte is far from the only company that has benefitted from CIRM’s early and consistent support. This year alone CIRM-funded companies have raised more than $1.0 billion in funding from outside investors; a clear sign of validation not just for the companies and their therapies, but also for CIRM and its judgement.
Humacyte raising $225 million for its program to help people battling kidney failure
Forty Seven Inc. raising $113 million from an Initial Public Offering for its programs targeting different forms of cancer
We have shown there is a path through the Valley of Death. We are hoping to lead many more companies through that in the coming years, so they can bring their therapies to people who really need them, the patients.
For years chemotherapy has been a mainstay in the war against cancer. While it can be very effective it can also come with some nasty side effects. Since chemo works by killing rapidly growing cells, it not only hits the cancer cells, but can also hit other rapidly growing cells too, including those in our hair roots, which is why many people undergoing chemo lose their hair.
So, the key to a truly effective anti-cancer therapy is one that does as much damage as possible to the cancer cells, and as little as possible to all the healthy cells in the body. A therapy being developed by Cellerant Therapeutics seems to have found that sweet spot in a new therapy targeting acute myeloid leukemia (AML).
AML starts in the bone marrow and quickly moves into the blood, where it can spread to other parts of the body. It is the second most common form of leukemia and claims around 10,000 lives in the US every year. Chemotherapy is the main weapon used against AML but it can also cause nausea, hair loss and other complications and in most cases has limited effectiveness because, over time, the leukemia cells get used to it.
In a study published in the journal Blood Advances, Cellerant researchers explain the limitations of existing treatments.
“The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy.”
Cellerant has developed a therapy called CLT030 which targets CLL1, a marker found on the surface of leukemia cells but not on normal blood stem cells. Preclinical studies in mice show CLT030 is able to zero in on this surface marker and attack the leukemia but do little damage to blood or other surrounding cells.
In a news release, Ram Mandalam, President and CEO of Cellerant, said this is encouraging news:
“AML remains a significant unmet medical need, and our therapy, CLT030, that can target leukemic stem cells precisely while minimally affecting normal hematopoietic stem cells could improve outcomes while avoiding much of the toxicities associated with conventional chemotherapy and other targeted therapeutics.”
Mandalam says they are now doing the late-stage preclinical testing to be able to apply to the Food and Drug Administration for permission to start a clinical trial. CIRM is funding this stage of the research.