CAR T-cell therapy: Hear from a Canadian patient – CTV News

TORONTO -- Owen Snider was given as little as three months to live. His blood cancer had returned and the prognosis was not good. The news, delivered over the phone during the height of the early pandemic lockdown in spring 2020, was devastating.

The Ottawa-area retiree began putting his affairs in order, preparing for what appeared to be inevitable.

It was terrible, his wife Judith Snider told CTV News. But we finally decided that what we had to do was to live each day not to look forward to the end, but to look forward to tomorrow.

And yet, a year later, Snider is alive -- transformed, even -- and his non-Hodgkins lymphoma is in remission. His second chance is all thanks to a promising, Canadian-run program for cancer treatment called CAR T-cell therapy.

Snider became one of the first patients to participate in a national research program that is assessing whether this experimental treatment can be done safely in Canada and cheaper than in the U.S., where costs can run upwards of half a million dollars per patient.

I think I am a pretty successful lab rat, Snider, who previously endured chemotherapy treatments and a stem cell transplant, said in an interview.

Thirty days after treatment, the lymphoma was gone. So how can you not be happy about that?

CAR T-cell therapy is a type of gene therapy that trains or engineers a patients own immune system to recognize cancerous cells. A type of white blood cell, called a T-cell, is a key component of a bodys immune system. They are developed from stem cells in the bone marrow and help fight infection and disease by searching and targeting specific foreign substances, known as antigens, in the body.

The protein receptors on T cells bind to the protein antigens on the surfaces of foreign particles that fit those receptors, like a lock and key. The foreign substance is eradicated once their antigens are bound to a T-cell. But blood cancer cells are normal cells that undergo mutations, so they are not recognized as a foreign threat to the body. In other words, T-cells generally do not have the right receptor key to fit with the antigens of a cancer cell.

CAR T-cell therapy modifies the cells so they are able to identify the cancer cells and destroy them. Its a labour-intensive process that involves taking blood from a patient and separating the T-cells. Then scientists add a gene to the cells that gives them instructions to develop an artificial receptor called a chimeric antigen receptor, or CAR.

We actually take the T-cells out and we modify them in the lab and put them back into the patient. So now they're able to recognize the cancer and kill it off, explained Dr. Kevin Hay, Medical Director for Clinical Cell Therapy with BC Cancer.

I think we're just at the cusp of really understanding what this is going to do for patients in the future.

The therapy is a labour-intensive process -- Snider's cells were shipped to Victoria, B.C to be processed in a special lab facility, then shipped back to Ottawa about a week later, where they were infused back into his body.

The treatment is still being studied, but is already available for some cancers in the U.S. and Canada at a steep price.

Researchers began trials in Canada in 2019 to see if it could be done domestically at a lower cost, highlighting the importance of having key medical production and therapies available in Canada.

We knew we had to do domestic manufacturing and if we've learned anything from COVID-19, it's that domestic capability is really important when it comes to science and medicine, and this is a perfect example of that, said Dr. Natasha Kekre, a hematologist and lead researcher on the trail based at the Ottawa Hospital.

Progress was impacted slightly by the pandemic, but Snider was fortunate enough to participate and is the first patient to come forward to discuss their experience and why he hopes the program will expand across Canada to help others dealing with otherwise untreatable forms of cancer.

Scientists are hoping to release more data in the coming months -- more than 20 patients have been treated so far, according to Dr. Kekre.

This is hopefully just the beginning for us. So this first trial was a foundation to prove that we could actually manufacture T cells, that we could do this in a clinical trial. And so this trial will remain open for patients who are in need, she said.

So absolutely we feel like were opening a door.

Snider's first experience with cancer treatment was more than a decade ago, in 2010, when he underwent a powerful and aggressive chemotherapy regimen that helped him stay cancer-free for six years.

But the treatment was so harsh that when his cancer came back in 2016, doctors told him he could not go through that kind of chemotherapy again. Instead, Snider underwent a stem cell transplant, which gave him another four years without cancer, until April 2020.

This time the outlook was grim, so doctors decided to try and get him into the CAR T-cell trials that started just before the pandemic hit. The study was specifically for patients with acute lymphoblastic leukemia and non-Hodgkins lymphoma who were not responding to other treatments.

Snider said the entire process was a walk in the park compared to what he had gone through before. He was given a mild chemotherapy treatment for three days while his T-cells were being modified in a lab on the other side of the country.

[The T-cells] went to work right away. There's a period of time where there's a lot going on inside fighting each other and that sort of thing. You don't feel great or you don't really know how you feel, Snider described. The treatment was met with outstanding success.

And in 30 days, there was no lymphoma. I couldn't believe it.

For Dr. Kekre, the results bring hope. Snider has done quite well and does not have any evidence of lymphoma at the moment, she said.

I'm unfortunately in a business where I often have to give bad news, and it is really motivating and exciting to be able to offer therapies to patients who didn't have options and to make them better, she said.

The trial is currently at the stage where scientists are making sure the product remains safe. Side-effects can include neurotoxicity, which harms the nervous system, and cytokine release syndrome, which triggers an acute system-wide inflammatory response that can result in organs not functioning properly. But so far researchers have, for the most part, been able to manage and reverse any side effects.

With such promising outcomes for patients who otherwise had no options left, researchers are talking about expanding these studies across Canada and to other forms of cancer. For now, the lab in Victoria is the only facility equipped to make these cell modifications.

I think its really going to be revolutionary with how we treat cancer in the future, not just blood cancers, but all cancers, said Dr. Hay.

Today, Snider is healthy and strong, even able to chop wood at his home near Ottawa. He and his wife Judith, a retired federal judge, are enjoying life anew.

It certainly has given us a future that we didnt know we had, she said.

The treatment not only bought Snider extra time, but also significantly improved his quality of life.

What was given to me is practically a normal life, he added.

It's really just transformed, not just extended, but transformed my life.

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CAR T-cell therapy: Hear from a Canadian patient - CTV News

Treatment Sequencing Could Change With Complementary Combinations and CAR T Options in B-ALL – OncLive

Significant progress with rapidly evolving therapies, including blinatumomab, inotuzumab ozogamicin, and CAR T-cell therapy, has been made to extend the median overall survival and improve outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

Significant progress with rapidly evolving therapies, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and chimeric antigen receptor (CAR) T-cell therapy, has been made to extend the median overall survival (OS) and improve outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Antibody-based therapies and CAR T-cell therapies are not mutually exclusive, according to Elias Jabbour, MD, who added that competitive options have the potential to be complementary if sequenced earlier.

Until recently, when somebody with ALL relapsed, the outcomes were bad and we didnt have anything [available to treat them], said Jabbour, a professor of medicine in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, in an interview with OncLive. Jabbour previewed his presentation on the practice-changing updates in relapsed/refractory B-ALL.

Over the past few years, weve [had] several options [become] available to our patients, [including] the bispecific engagers, antibody-drug conjugates [ADCs], and CAR T-cell therapies, first for pediatric and [adolescent and] young adult [AYA] patients and now for adult patients. Each [therapy] has shown a benefit when compared with standard of care. The question is: How do we optimize the [options] to improve outcomes in ALL? Jabbour asked.

Although not yet backed by level 1 evidence, a potentially promising therapeutic sequencing strategy could incorporate blinatumomab in combination with inotuzumab ozogamicin as frontline therapy followed by consolidative CAR T-cell therapy, Jabbour explained. He added that this strategy could begin to phase out the use of allogeneic stem cell transplant and chemotherapy in B-ALL because these approaches may not be optimal following CAR T-cell therapy.

Each [option] alone is not great enough. The value of treatment can be further improved, Jabbour said. This way we can offer these treatments, which are expensive and not [widely] available, in the most optimal way. We can improve the cure rate instead of giving every agent alone with minimal or acceptable benefit.

Over several decades, the 5-year OS rate for patients with ALL has increased from 26% between 1984 and 1989 to 59% between 2010 and 2019. Reasons for this success include the addition of TKIs like ponatinib (Iclusig) with or without blinatumomab to chemotherapy-based regimens in patients with Philadelphia chromosomepositive ALL, the addition of rituximab (Rituxan) to chemotherapy in Burkitt and preB-ALL, and the use of CAR T-cell therapy in B-ALL. Additionally, although still being fleshed out, the importance of minimal residual disease (MRD) as a predictive marker for progression has become understood in recent years.

In 2017, the FDA granted a full approval to the monoclonal antibody blinatumomab for the treatment of adult and pediatric patients with relapsed/refractory B-cell precursor ALL.1 The approval was based on findings from the phase 3 TOWER trial (NCT02013167), in which blinatumomab elicited a 44% complete remission (CR) with full, partial, or incomplete hematologic recovery (CRi) rate vs 25% with standard of care chemotherapy (P < .001).2 The median OS was 7.7 vs 4 months, respectively (HR, 0.71; 95% CI, 0.55-0.93; P = .01).

Another phase 3 study (NCT02101853) evaluated blinatumomab vs chemotherapy in children and AYA patients with B-ALL in first relapse.3 The 2-year disease-free survival rate was 54.4% with blinatumomab vs 39% with chemotherapy (HR, 0.70; 95% CI, 0.47-1.03; P = .03). The 2-year OS rates were 71.3% vs 58.4%, respectively (HR, 0.62; 95% CI, 0.39-0.98; P = .02).

Also in 2017, the ADC inotuzumab ozogamicin was approved by the FDA for the treatment of adults with relapsed/ refractory B-cell precursor ALL based on findings from the phase 3 INO-VATE trial (NCT01564784).4 Updated results showed a 73.8% CR/CRi rate with inotuzumab ozogamicin vs 30.9% with standard-of-care chemotherapy in this patient population (P < .0001).5

In an ongoing phase 1/2 study (NCT01371630), inotuzumab ozogamicin in combination with low-intensity minihyper-CVD (mini-HVCD), a chemotherapy regimen consisting of cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 for4 doses, demonstrated encouraging activity in patients with relapsed/ refractory Philadelphia chromosomenegative ALL.6

Long-term follow-up data from the study showed an overall response rate of 80% with inotuzumab ozogamicin plus miniHVCD, with a complete response rate of 57% among 96 patients treated.7 The MRD negativity rate among responders was 83%.

To further expand this regimen, another study evaluated sequential inotuzumab ozogamicin with mini-HVCD with or without blinatumomab as salvage therapy for patients with ALL in first relapse.8 The results showed a median OS of 16.5 months with the combination as first-line salvage therapy and 5.8 months as second-line or later salvage therapy, indicating that salvage status affects OS, Jabbour said.

In 2017, the CAR T-cell therapy tisagenlecleucel (Kymriah) became the first gene therapy to be approved in the United States.9 The regulatory decision made the therapy available for use in pediatric and AYA patients with relapsed/refractory B-ALL.

Updated findings from the phase 2 ELIANA trial (NCT02435849) demonstrated a 24-month OS rate of 66% with tisagenlecleucel in this patient population.10 On October 1 another CAR T-cell product, brexucabtagene autoleucel (brexu-cel; Tecartus) was approved by the FDA for use in adult patients with relapsed/refractory B-ALL.11

adult patients with relapsed/refractory B-ALL.11 The decision was based on findings from the phase 1/2 ZUMA-3 trial (NCT02614066), in which a single infusion of brexu-cel elicited a high response rate consisting of durable responses in patients with heavily pretreated relapsed/refractory B-ALL.12-13

Of 54 patients in the efficacy population, 64.8% (95% CI, 51%-77%) of patients who received brexu-cel had a CR/CRi (Table13). Over half of patients (51.9%) obtained a CR. Moreover, the median duration of remission (DOR) was 13.6 months (95% CI, 9.4-not estimable [NE]). The median DOR for those who achieved CR was not reached (95% CI, 9.6-NE) and the median DOR for those who achieved CRi was 8.7 months (95% CI, 1.0-NE).13

In previously reported data, nearly all responders (97%) had MRD negativity after treatment with brexu-cel. Regarding safety, grade 3 or higher cytokine release syndrome occurred in 24% of patients who received brexucel. Grade 3 or higher neurologic toxicities occurred in 25% of patients.12

We just started the journey with CAR T-cell therapy. There is no question that our management of toxicity will improve. We will gain more expertise, so what we see today may not be the case in 5 to 6 years, Jabbour said.

Jabbour also highlighted that accessibility remains another challenge of CAR T-cell therapy that needs to be overcome. The accessibility [of CAR T-cell therapy] is a problem today, but ALL is [also] a rare disease. We can only become experts if we have patients, Jabbour added.

Id like to know where CAR T-cell therapy benefits patients most. Activity has been shown across refractory populations, but we know that outcomes can be better in patients with minimal to no disease. That is where I see a role for CAR T-cell therapy. I try to cytoreduce and give CAR T-cell therapy after to offer the best outcomes, Jabbour said.

Capitalizing upon the success demonstrated with CAR T-cell therapy, research efforts are under way to evaluate improved CAR T-cell therapy designs, dual targeting CAR T-cell therapies, allogeneic products, and fractionated CAR T-cell therapies, Jabbour explained. Notably, CAR T-cell therapy could largely replace the need for allogeneic stem cell transplant for patients with B-ALL who have MRD in first remission.

We are in the best [era because] we have the tools to cure ALL. Everything is ready in our hands. The future involves using less chemotherapy but more targeted approaches. Some of [the targeted options] are in the refractory field right now, but they are moving rapidly to the frontline setting to change the field, Jabbour concluded.

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Treatment Sequencing Could Change With Complementary Combinations and CAR T Options in B-ALL - OncLive

Talaris therapy ends need for immune drugs in transplant patients – – pharmaphorum

Two kidney transplant patients who received a stem cell therapy developed by Talaris Therapeutics were able to come off all immunosuppressant drugs within a year, without any evidence of graft rejection.

The first findings from Talaris phase 3 trial of the cell therapy called FCR001 suggest it may be possible to eliminate the need entirely for patients to take what may be dozens of tablets daily after organ transplants, according to the US biotech.

While still preliminary, the experience with the two patients back up Talaris hope that giving a one-shot dose of FCR001 the day after an organ transplant could stimulate immune tolerance in the recipient, and avoid the side effects of current drug treatments such as infections, heart disease, and some forms of cancer.

The companys approach relies on administering haematopoietic stem cells from the individual who donated the organ, in order to generate what Talaris refers to as chimerism, with both donor and recipient cells present in the bone marrow. That allows the immune system to see the transplanted organ as self rather than foreign.

The first two recipients in Talaris FREEDOM-1 phase 3 trial had received FCR001 at least 12 months earlier, and showed stable kidney function, according to Talaris.

A larger group of five patients who were at least three months from the cell therapy maintained more than 50% chimerism in their T cells, which the biotech said was a sign of long-term, immunosuppression-free tolerance to the donated kidney in its phase 2 trials.

The FREEDOM-1 results reported at the American Society of Nephrology (ASN) meeting this week were accompanied by updated results from Talaris phase 2 study, in which all 26 patients originally weaned off immunosuppressants have continued to remain off them without rejecting their donated kidney.

Some transplant patients treated with Talaris therapy in earlier trials have now been off all immunosuppression for more than 12 years without signs of kidney rejection.

Talaris intends to enrol 120 subjects into the phase 3 trial, which is scheduled to generate results in 2023.

Earlier this year, Talaris raised $150 million via a Nasdaq listing that will be used to take FCR001 through the phase 3 programme in organ transplantation and as a treatment for rare autoimmune disease scleroderma.

It also recently started a phase 2 trial of the cell therapy to see if it is able to induce immune tolerance to a transplanted kidney in patients who received the transplant from a living donor up to a year prior to administration of FCR001.

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Talaris therapy ends need for immune drugs in transplant patients - - pharmaphorum

Studies: CAR-T therapies superior to standard treatment in blood cancer – STAT

On Covid-19 booster shots, the FDA has overstepped its

On Covid-19 booster shots, the FDA has overstepped its role

Comparing the Covid-19 vaccines developed by Pfizer, Moderna, and

Comparing the Covid-19 vaccines developed by Pfizer, Moderna, and Johnson & Johnson

Why fentanyl is deadlier than heroin, in a single

Why fentanyl is deadlier than heroin, in a single photo

New court rulings add to the confusing and controversial

New court rulings add to the confusing and controversial dispute over a U.S. drug discount program

The hurried push by Congress to address drug costs

The hurried push by Congress to address drug costs shouldnt undermine the vast savings from generics

Clinical trial sites face challenges in diversifying personnel and

Clinical trial sites face challenges in diversifying personnel and participants, study finds

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Studies: CAR-T therapies superior to standard treatment in blood cancer - STAT

Parkinson’s gene therapy restores responses to dopamine-boosting drug in mouse models – FierceBiotech

Levodopa, the commonly prescribed dopamine-restoring drug for Parkinson's disease, loses its effectiveness over time. Researchers at Northwestern University say they've found a potential method forreviving the drug's benefits: gene therapy.

The researchers restored the ability of neurons to convert levodopa into dopamine in mice with a gene therapy that targets the substantia nigra region of the brain. By effectively recreating a healthy environment in the brain, the therapy eliminated abnormal brain activity that causes movement difficulties in Parkinson's patients, the teamreported in Nature.

The new findings also provided insights into why dopamine-releasing neurons wither away in Parkinson's. By studying the genetic features of theneurons in Parkinson's models, the Northwestern researchers showed that damage to the mitochondria, the power suppliers inside of dopamine-producing neurons, triggers events that lead to Parkinson's.

"Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons," said James Surmeier, Ph.D., chair of neuroscience at Northwestern's Feinberg School of Medicine, in a statement.

Theinsights could be usedto develop tests that identify Parkinson'sin people five to 10 years before it manifests, Surmeier suggested.

RELATED:Neurocrine exits $165M Parkinson's pact with Voyager after FDA hold

Efforts to develop gene and cell therapies for Parkinson's are underway, with mixed results so far.Bayer has started two early-stage trials: a gene therapy being developed byits subsidiary AskBio and a stem cell treatment from its unit BlueRock Therapeutics.

Voyager Therapeutics has suffered several setbacks in its efforts to develop a gene therapy for Parkinson's.Sanofi ended its deal with Voyager in October 2017, AbbVie nixed its pact in August 2020 and Neurocrine Biosciences axed its tie-up in February of this year after a clinical hold was placed on a phase 2 trial last December. Pfizer inkeda $630 million pact with Voyager last month to use its capsids in neurologic and cardiovascular gene therapies, though the specific disease targets were not disclosed.

Other researchers are also looking for innovative ways to spruce up dopamine-producing neurons. A team at the University of San Diego, California developeda gene therapy technique that turned astrocyte cells into dopamine-producing neurons, for example.

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Parkinson's gene therapy restores responses to dopamine-boosting drug in mouse models - FierceBiotech

Salit Discusses the Use of Staging and Grading for Patients With GVHD to Choose Appropriate Treatment – Targeted Oncology

Rachel B. Salit, MD, discussed the case of a 48-year-old patient with graft-versus-host-disease.

Rachel B. Salit, MD, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center at the University of Washington School of Medicine in Seattle, WA, discussed the case of a 48-year-old patient with graft-versus-host-disease.

Targeted OncologyTM: What are your thoughts on the currently accepted options for acute GVHD (aGVHD) prophylaxis?

SALIT: Between calcineurin inhibitors, if we have a choice, my preference is usually tacrolimus. Tacrolimus is better tolerated [than cyclosporin] in terms of adverse events [AEs], blood pressure, kidney function, and [even] the smell.

Methotrexate is a tried-and-true prophylaxis, especially in the myeloablative or high-intensity transplant setting. [In contrast], mycophenolate mofetil [MMF]; [CellCept] is usually used in the nonmyeloablative or reduced-intensity setting. When calcineurin inhibitors were used with MMF as prophylaxis for GVHD, the GVHD was higher. Thats why we [use] methotrexate [instead of MMF].1

Sirolimus [Rapamune] is often combined with a calcineurin inhibitor and MMF, or with a calcineurin inhibitor and methotrexate. Sirolimus is very well tolerated, except for some triglyceride AEs. Additionally, the combination of sirolimus plus MMF and a calcineurin inhibitor has been shown to significantly decrease GVHD in the reduced-intensity setting compared with [the effect observed with] MMF and a calcineurin inhibitor alone.2

CAR [chimeric antigen receptor] T-cellantibody therapy plus antithymocyte globulin [ATG] and alemtuzumab [Lemtrada] are more frequently used in Europe [than in the United States]. There have been mixed results, and there is some concern of increased relapse with [anti-thymocyte globulin (ATG) therapy]. Ex vivo T-cell depletion and CD34-positive cell selection [are] also uncommon in the United States.

Posttransplant cyclophosphamide [Cytoxan] [is becoming more common], and it was originally [used in the setting of] haploidentical transplants. Now it is increasingly used in the unrelated donor setting, and Im sure it will be translated to the sibling setting, too. [This regimen] has been shown to decrease effector T cells.3 Moreover, chronic GVHD is [reduced by this regimen], but aGVHD is not changed.

A recent study retrospectively compared many patients [with haploidentical donors] to a smaller number of patients [who had] unrelated donors and who received posttransplant cyclophosphamide. The data showed that the patients with unrelated donors and posttransplant cyclophosphamide had better overall survival [OS] and decreased relapse compared with the patients with haploidentical donors.4

For a long time, [most trials that compared GVHD and OS between patients with haploidentical] vs unrelated or sibling donors have shown that posttransplant [cyclophosphamide in the setting of haploidentical] transplants is associated with reduced chronic GVHD, but the other outcomes were the same. Is this result attributable to the fact that the transplant is haploidentical, or is it attributable to the posttransplant cyclophosphamide? I think that question will be answered within the next [few] years.

What risk factors for GVHD do you notice in the case described?

There are multiple risk factors. The fact that the donor is multiparous puts the recipient at higher risk for GVHD. The patients high intensity, myeloablative conditioning regimen increases the risk for GVHD, as do the donors CMV seropositivity and the fact that the patient and donor are not sex matched. The risk of GVHD also increases with donor age.

Risk for GVHD is also increased by major human leukocyte antigen [HLA] disparity. We look at class I [HLA-A, -B, and -E] and class II [HLA-DR and -DQ] antigens, with a 10 out of 10 score constituting a match. There are data coming out that show that the class II antigen HLA-DP also matters in certain cases5; a match that includes this antigen [a 12 out of 12 (score)] is better than a 10 out of 10 [score]. [This patients donor was HLA-matched, but] minor HLA mismatches can increase the risk of GVHD [in patients like this one whose donor is unrelated].

Stem cell source and graft composition are other considerations, but this patient received peripheral blood, which confers a higher risk of GVHD than does bone marrow. Peripheral blood has a higher CD34-positive cell count, therefore a higher T-cell dose; both factors increase GVHD risk. At our center, we dont often cap CD34-positive cell count or T-cell dose, except in the haploidentical setting.

I would not include ABO blood type as a risk factor. There are mixed data regarding whether major and minor ABO mismatches lead to increased GVHD.6

What standardized guidelines exist for organ staging and grading in the context of aGVHD?

[According to Mount Sinai Acute GVHD International Consortium], the skin, the liver, and gastrointestinal [GI] tract are the 3 organs included in aGVHD staging. The skin is [described in terms of] the percentage of body surface area [BSA] affected. Stage 0 is no rash, stage 1 is a rash covering less than 25% of the BSA, stage 2 is a rash covering 25% to 50% of the BSA, stage 3 is a rash covering greater than 50% of the BSA, and stage 4 is generalized erythroderma.7

According to the liver status [bilirubin level], staging starts at stage 0 [less than 2 mg/dL] and progresses through stage 1 [2-3 mg/dL], stage 2 [3.1-6 mg/dL], and stage 3 [6.1-15 mg/dL] to a final stage of 4 [greater than 15 mg/dL]. The lower GI staging system [counts] the number of episodes per day of liquid stool output. Stage 0 is fewer than 3 episodes [of stool output], stage 1 is 3 to 4 episodes, stage 2 is 5 to 7 episodes, and stage 3 is greater than 7 episodes. If you have an inpatient, then you can use these exact quantities. If you have an outpatient, you can use these values as rough markers. Regarding the upper GI staging system, in stage 0, nausea, vomiting, or anorexia are absent or intermittent, but in stage 1, they are persistent.

The other thing I often look at [to judge] severity [of GI involvement] is the electrolytes. For example, if the patient says they are having 5 episodes of stool a day, but their potassium and magnesium are normal and theyre not becoming acidemic, then you [might consider that] these stools are only of small volume. If the patient starts to have electrolyte abnormalities or starts to become acidemic, then you [should consider that] maybe theyre having more diarrhea than theyre [telling you].

When we grade according to most severe target organ involvement, grade I reflects the presence only of stage 1 to 2 skin involvement. Any GI or liver involvement is automatically [at least grade] II, the point at which you would consider treating symptoms topically. Grade IIA indicates upper GI involvement, and grade IIB indicates lower GI involvement.8 Once the patient gets to grade III, they almost always [require] systemic therapy.7

What stage and grade would you give this patient?

With 60% skin involvement, he would have a skin stage of 3, and with 4 episodes of diarrhea per day, he would have a lower GI stage of 1. [He would have an overall clinical grade of IIB.]

What are GVHD and aGVHD biomarkers, and how are they used?

Biomarkers of GVHD are markers of inflammation found in the blood that will tell you the patient is at a higher risk for developing GVHD. These biomarkers include elafin, IL-2 receptor-, IL-8, tumor necrosis factor receptor-1, hepatocyte growth factor, and regenerating islet-derived 3- [NCT00224874].9 The use of biomarkers [to predict patients risk of developing GVHD could guide physicians as they choose] a starting steroid dosage, eg, 2 mg/kg vs 1 mg/kg.

What data guide your decisions about steroid therapy in GVHD?

Although the concept of GVHD and aGVHD risk stratification is not generally used in practice, high-risk GVHD vs standard-risk GVHD has been shown to be associated with a lower rate of complete response to steroids [27% vs 48%, respectively; P < .001] and higher treatment-related mortality [incidence at 6 months after steroid therapy onset, 44% vs 22%, respectively; P < .001].10 If a patient has a higher grade of GVHD, they are more likely to be steroid refractory.

The steroid response of GVHD is classified as steroid refractory or resistant if GVHD progresses within the first 3 to 5 days of prednisone therapy onset [ 2 mg/kg per day], fails to improve within 5 to 7 days of treatment initiation at 1 mg/kg or shows an incomplete response after more than 28 days [of immunosuppressive treatment including steroids]. Steroid dependence [means that either] the prednisone cannot be tapered below 2 mg/kg daily or the GVHD recurs during the steroid taper.11

You cant really [know] who is going to respond to steroids without [trying]. Our initial treatment for any patient with GVHD is steroids. There are no data to suggest that we [should] add something other than steroids as the first line or that we [should] add double therapy for the first line. Its going to be different for every individual.

Also, regarding steroid therapy, the question has been raised: If patients receive higher doses sooner, will that result in a lower [total] exposure to steroids? In the study we did at our institution, we found that when patients with skin GVHD were randomly assigned [to receive] 1 mg/kg vs 0.5 mg/kg, patients [who received the lower dose] had a longer and higher overall exposure to steroids.12 [In cases of skin GVHD], we tend to undertreat patients, and it may help to give them at least 1 mg/kg, but for GI GVHD, we usually give 1 mg/kg. It may not help to give 2 mg/kg unless the GVHD is severe.

Other than steroids, what therapy options exist for aGVHD, according to the National Comprehensive Cancer Network (NCCN)?

Ruxolitinib [Jakafi] is the only approved therapy, and it is supported by category 1 evidence. Some other therapies, such as MMF and sirolimus, are [relatively] benign. Other treatments, like ATG, are more toxic, whereas extracorporeal photopheresis [ECP] doesnt have a lot of data [to support it]. However, we do use a lot of ECP, [primarily for] steroid-dependent GVHD of the skin.13

What data support the use of ruxolitinib for aGVHD?

In the REACH1 study [NCT02953678], patients with steroid refractory grade 2 to 4 aGVHD received ruxolitinib, 5 mg twice a day. Later, patients could increase to 10 mg twice a day.14,15

The overall response rate [ORR] at day 28 was about 55%. The best ORR at any time during treatment was 73%. Time to response was about 7 days [range, 6-49]. The median duration of response was almost a year. Death from causes other than malignancy relapse was found in about 50% of patients. The median OS was about 5 months, whereas median OS for steroid refractory GVHD was 1 month, [but median OS for day 28 responders was not reached].16,17 The overall response rate [ORR] at day 28 was about 55%. The best ORR at any time during treatment was 73%. Time to response was about 7 days [range, 6-49]. The median duration of response was almost a year. Death from causes other than malignancy relapse was found in about 50% of patients. The median OS was about 5 months, whereas median OS for steroid-refractory GVHD was 1 month, [but median OS for day 28 responders was not reached].15

The ORR at day 28 was 62% in the ruxolitinib group vs 39% in the control group [odds ratio (OR), 2.64; 95% CI, 1.65-4.22; P < .001]; the durable ORR at day 56 was 40% in the ruxolitinib group vs 22% in the control group [OR, 2.38; 95% CI, 1.43-3.94; P < .001].18 These results led to the FDA approval of ruxolitinib for second-line therapy for steroid-refractory aGVHD.19

[Separate analyses were conducted of] GI and skin GVHD. In the ruxolitinib group, aGVHD staging of the lower GI was stage 3 and 4 for most patients at baseline. This was reduced in most patients to stage 0, 1, and 2 by day 28. In contrast, most patients treated with BAT still presented with stage 2 to 4 GVHD by day 28. Likewise for the skin, the GVHD stage was more likely to decrease following treatment with ruxolitinib than with BAT.19

Median failure-free survival was 5 months in the ruxolitinib group vs 1 month in the BAT group [HR, 0.46; 95% CI, 0.35-0.60]; 5 months was a big achievement compared with our previous standard. After 1 year, 40% of the patients in the experimental group were still alive. Regarding AEs associated with ruxolitinib, the most difficult [AE to manage] is thrombocytopenia [in REACH2, affecting 33% of the ruxolitinib group vs 18% of the BAT group]. Infections with ruxolitinib [in the context of GVHD] probably are equivalent to [those observed with] any other immune suppression drug [for cytomegalovirus, 26% in the ruxolitinib group, 21% in the BAT group].19

REFERENCES:

1. Yoshida S, Ohno Y, Nagafuji K, et al. Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation. Ann Hematol. 2019;98(11):2579-2591. doi:10.1007/s00277-019-03801-z

2. Bejanyan N, Rogosheske J, DeFor TE, et al. Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free graft-versus-host disease prophylaxis for reduced-intensity conditioning umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2016;22(11):2025-2030. doi:10.1016/j. bbmt.2016.08.005

3. Wodarczyk M, Ograczyk E, Kowalewicz-Kulbat M, Druszczyska M, Rudnicka W, Fol M. Effect of cyclophosphamide treatment on central and effector memory T cells in mice. Int J Toxicol. 2018;37(5):373-382.

4. Shaw BE. Related haploidentical donors are a better choice than matched unrelated donors: counterpoint. Blood Adv. 2017;1(6):401-406. doi:10.1182/bloodadvances.2016002188

5. Zachary AA, Leffell MS. HLA mismatching strategies for solid organ transplantation - a balancing act. Front Immunol. 2016;7:575. doi:10.3389/ fimmu.2016.00575

6. Brierley CK, Littlewood TJ, Peniket AJ, et al. Impact of ABO blood group mismatch in alemtuzumab-based reduced-intensity conditioned haematopoietic SCT. Bone Marrow Transplant. 2015;50(7):931-938. doi:10.1038/bmt.2015.51

7. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-vs-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001

8. Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30-37. doi:10.1182/blood-2016-07-686642

9. Levine JE, Logan BR, Wu J, et al. Acute graft-vs-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012;119(16):3854-3860. doi:10.1182/blood-2012-01-403063

10. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-vs-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001

11. Schoemans HM, Lee SJ, Ferrara JL, et al; European Society for Blood and Marrow Transplantation [EBMT] Transplant Complications Working Party; EBMT-National Institutes of Health [NIH]-Center for International Blood and Marrow Transplant Research [CIBMTR] GVHD Task Force. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-vs-host disease assessment. Bone Marrow Transplant. 2018;53(11):1401-1415. doi:10.1038/s41409-018-0204-7

12. Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica. 2015;100(6):842-848. doi:10.3324/haematol.2014.118471

13. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 5.2021. Accessed October 13, 2021. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf

14. Chao N. Finally, a successful randomized trial for GVHD. N Engl J Med. 2020;382(19):1853-1854. doi:10.1056/NEJMe2003331

15. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, von Bubnoff N. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10(5):391-402. doi:10.2217/ imt-2017-0156

16. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823

17. Jagasia M, Ali H, Schroeder MA, et al. Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease: results from the phase 2 REACH1 trial. Biol Blood Marrow Transplant. 2019;25(suppl 3):S52. doi:10.1016/j.bbmt.2018.12.130

18. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-vs-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635

19. Przepiorka D, Luo L, Subramaniam S, et al. FDA approval summary: ruxolitinib for treatment of steroid-refractory acute graft-versus-host disease. Oncologist. 2020;25(2):e328-e334. doi:10.1634/theoncologist.2019-0627

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Salit Discusses the Use of Staging and Grading for Patients With GVHD to Choose Appropriate Treatment - Targeted Oncology

Orchard Therapeutics Reports Third Quarter 2021 Financial Results and Highlights Recent Business Updates – BioSpace

Updates from OTL-201 Clinical Proof-of-Concept Study in MPS-IIIA and OTL-204 Preclinical Study for GRN-FTD at ESGCT Showcase Potential for HSC Gene Therapy in Multiple Neurodegenerative Disorders

Launch Activities for Libmeldy Across Key European Countries, including Reimbursement Discussions, Progressing in Anticipation of Treating Commercial Patients

Frank Thomas, President and Chief Operating Officer, to Step Down Following Transition in 2022; Search for a Chief Financial Officer Initiated

Cash and Investments of Approximately $254M Provide Runway into First Half 2023

BOSTONandLONDON, Nov. 04, 2021 (GLOBE NEWSWIRE) --Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today reported financial results for the quarter ended September 30, 2021, as well as recent business updates and upcoming milestones.

This quarter, we are pleased by the progress demonstrated by our investigational neurometabolic HSC gene therapy programs with promising preclinical and clinical updates at ESGCT, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. With follow-up in OTL-201 for MPS-IIIA patients now ranging between 6 and 12 months, biomarker data remain highly encouraging, showing supraphysiological enzyme activity and corresponding substrate reductions in the CSF and urine. The launch strategy for Libmeldy is also advancing in Europe with momentum building on reimbursement discussions and patient finding activities.

Recent Presentations and Business Updates

Data presentations at ESGCT

Clinical and pre-clinical data from across the companys investigational hematopoietic stem cell (HSC) gene therapy portfolio were featured in two oral and seven poster presentations at the European Society of Gene & Cell Therapy Congress (ESGCT) on October 19-22. Highlights from key presentations are summarized below:

R&D Investor Event Summary

In September, Orchard hosted an R&D investor event highlighting its discovery and research engine in HSC gene therapy, including an update on the OTL-104 program in development for NOD2 Crohns disease (NOD2-CD) and potential new applications in HSC-generated antigen-specific regulatory T-cells (Tregs) and HSC-vectorization of monoclonal antibodies (mAbs).

The discussion also covered the differentiated profile of Orchards HSC gene therapy approach, which has exhibited favorable safety, long-term durability and broad treatment applicability.

Libmeldy (atidarsagene autotemcel) launch in Europe

Orchard is providing an update on the following key launch activities for Libmeldy in Europe:

Executive organizational update

The company also announced that Frank Thomas will step down from his role as president and chief operating officer, following a transition in 2022. A search for a chief financial officer is underway. Mr. Thomas other responsibilities will be assumed by existing members of the leadership team in commercial and corporate affairs. Orchard recently strengthened the executive team with the appointments of Nicoletta Loggia as chief technical officer and Fulvio Mavilio as chief scientific officer and the promotion of Leslie Meltzer to chief medical officer.

I want to extend my gratitude to Frank Thomas for his immense contributions to Orchard, said Gaspar. During his tenure, Frank oversaw the transition of the organization to a publicly traded company and has managed operations with a focus on cross-company innovation, including his role as a key architect in creating and executing the focused business plan we rolled out in 2020. Along with the entire board of directors and leadership team, I appreciate Franks commitment to facilitate a smooth transition during this time.

Gaspar continued, Our search is focused on a CFO to lead the broad strategic planning efforts necessary to capitalize on the full potential of our hematopoietic stem cell gene therapy platform. We have a strong team in place to aid Orchards success in this next phase of growth and are well capitalized through the anticipated completion of several value-creating milestones.

Upcoming Milestones

In June 2021, Orchard announced several portfolio updates following recent regulatory interactions for the companys investigational programs in metachromatic leukodystrophy (MLD), Mucopolysaccharidosis type I Hurler syndrome (MPS-IH) and Wiskott-Aldrich syndrome (WAS).

Third Quarter 2021 Financial Results

Revenue from product sales of Strimvelis were $0.7 million for the third quarter of 2021 compared to $2.0 million in the same period in 2020, and cost of product sales were $0.2 million for the third quarter of 2021 compared to $0.7 million in the same period in 2020. Collaboration revenue was $0.5 million for the third quarter of 2021, resulting from the collaboration with Pharming Group N.V. entered into in July 2021. This revenue represents expected reimbursements for preclinical studies and a portion of the $17.5 million upfront consideration received by Orchard under the collaboration, which will be amortized over the expected duration of the agreement.

Research and development (R&D) expenses were $20.8 million for the third quarter of 2021, compared to $14.7 million in the same period in 2020. The increase was primarily due to higher manufacturing and process development costs for the companys neurometabolic programs and lower R&D tax credits as compared to the same period in 2020. R&D expenses include the costs of clinical trials and preclinical work on the companys portfolio of investigational gene therapies, as well as costs related to regulatory, manufacturing, license fees and development milestone payments under the companys agreements with third parties, and personnel costs to support these activities.

Selling, general and administrative (SG&A) expenses were $13.0 million for the third quarter of 2021, compared to $13.0 million in the same period in 2020. SG&A expenses are expected to increase in future periods as the company builds out its commercial infrastructure globally to support additional product launches following regulatory approvals.

Net loss was $36.4 million for the third quarter of 2021, compared to $20.3 million in the same period in 2020. The increase in net loss as compared to the prior year was primarily due to higher R&D expenses as well as the impact of foreign currency transaction gains and losses. The company had approximately 125.5 million ordinary shares outstanding as of September 30, 2021.

Cash, cash equivalents and investments as of September 30, 2021, were $254.1 million compared to $191.9 million as of December 31, 2020. The increase was primarily driven by net proceeds of $143.6 million from the February 2021 private placement and $17.5 million in upfront payments from the July 2021 collaboration with Pharming Group N.V., offset by cash used for operating activities and capital expenditures. The company expects that its cash, cash equivalents and investments as of September 30, 2021 will support its currently anticipated operating expenses and capital expenditure requirements into the first half of 2023. This cash runway excludes an additional $67 million that could become available under the companys credit facility and any non-dilutive capital received from potential future partnerships or priority review vouchers granted by the FDA following future U.S. approvals.

About Libmeldy / OTL-200

Libmeldy (atidarsagene autotemcel), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.

Libmeldy is approved in the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the US.

Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.

About Orchard

At Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patients own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment.

In 2018, the company acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard has a deep pipeline spanning pre-clinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S. headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us onTwitterandLinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (TwitterandLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, the therapeutic potential of Libmeldy (OTL-200) and Orchards product candidates, including the product candidates referred to in this release, Orchards expectations regarding its ongoing preclinical and clinical trials, including the timing of enrollment for clinical trials and release of additional preclinical and clinical data, the likelihood that data from clinical trials will be positive and support further clinical development and regulatory approval of Orchard's product candidates, and Orchards financial condition and cash runway into the first half of 2023. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy, including the risk that Orchard may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2021, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

Investors Renee Leck Director, Investor Relations +1 862-242-0764 Renee.Leck@orchard-tx.com

Media Benjamin Navon Director, Corporate Communications +1 857-248-9454 Benjamin.Navon@orchard-tx.com

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Orchard Therapeutics Reports Third Quarter 2021 Financial Results and Highlights Recent Business Updates - BioSpace