Could Cancer Vaccines Be the Next Big Breakthrough in Immunotherapy?

Oncology remains the major focus area in R&D for large pharma companies as global spending in the area continues to grow. Immunotherapies, in particular, have quickly become some of the best-selling products on the market. Seeking ever more efficacious treatments, companies are now eyeing cancer vaccines, which experts say could be more powerful than other immunotherapies and may even provide a preventative measure against certain malignancies.

The first therapeutic cancer vaccine was approved in 2010, and Dendreon’s Provenge is still the only therapy of this type on the market. But interest in the space is growing as certain candidates enter late-stage clinical trials.

“It’s definitely a competitive area,” said Scot Ebbinghaus, vice president of clinical research at Merck, which is developing mRNA-4157/V940 in partnership with Moderna. “But competition is a good thing for patients. It makes us work harder and smarter. We look carefully at what our competitors are doing and keep this mind when we are developing our plans.”

Proving the Concept of Cancer Vaccines

Ebbinghaus explained that both cancer vaccines and immunotherapies, such as Merck’s blockbuster Keytruda (pembrolizumab), act on the T cells, which fight cancer. “The way PD-1 inhibitors work is they take the brakes off of those cells. The vaccines work by presenting tumor-specific antigens to the immune system, which activates even more anti-tumor T cells, potentially allowing pembrolizumab to have a stronger effect,” he told BioSpace.

Merck and Moderna’s vaccine is one of the most advanced candidates in development. mRNA-4157/V940 is currently being explored as a combination treatment with Keytruda, with Phase III trials underway in high-risk melanoma and non-small cell lung cancer (NSCLC). In Phase IIb trials for melanoma, the combination treatment was able to reduce the risk of recurrence or death by 49% compared to Keytruda alone.

“What we have seen so far suggests that these drugs could be really useful in patients who have had cancer surgery and preventing recurrence,” Ebbinghaus said. “This is a very large population of patients with an unmet need to reduce the risk of cancer recurrence.”

Another potential advantage of this therapeutic approach, based on the data the partners have seen so far, is that the safety profile is similar to that of standard vaccines, Ebbinghaus added. This means pain at the injection site or mild fever, which he said is preferable to the adverse events associated with chemotherapy. These milder adverse events could also allow the vaccines to be delivered in situations where a patient’s health does not allow for exposure to harsher treatments, he noted.

Some vaccine candidates in mid- to late-stage development, such as an mRNA product being pursued by BioNTech and Roche/Genentech, are being tested in combination with chemotherapy. Now in Phase II trials, the mRNA vaccine is administered along with Roche’s checkpoint inhibitor Tecentriq and chemo against pancreatic cancer.

Another company developing a portfolio of cancer vaccines is CureVac, which announced in April that it would collaborate with MD Anderson on early-stage research. A CureVac spokesperson told BioSpace over email that the company is developing two approaches: an “off-the-shelf” platform tailored to patients with specific cancer types, and a fully personalized approach that would be based on a patient’s individual tumor genomic profile.

The MD Anderson partnership is based on the first method and the tumor antigens shared across different cancer indications. The collaboration will use whole genome sequencing in combination with short- and long-read RNA sequencing to identify promising antigens, the spokesperson said, adding that the aim is to “go beyond the current state-of-the-art antigen space.”

Preventive Therapy

Along with the aforementioned therapeutic vaccines, research is also ongoing into developing preventive vaccines. The former are designed to treat an existing cancer, while the latter aim to help the immune system recognize and destroy cancer cells before they can gain a foothold in the body.

Cancer Research UK (CRUK) recently announced it would provide funding to researchers at the University of Oxford, the Francis Crick Institute and University College London to develop a preventive lung cancer vaccine. The research could lead to the first vaccine for people at high risk of developing the disease, such as current or previous smokers aged 55–74. The vaccine, known as LungVax, is based on the same technology that was employed in AstraZeneca’s COVID-19 vaccine.

Hattie Brooks, a science engagement manager at CRUK, explained how the vaccine could potentially work. “The vector has been modified to express a protein, known as a neoantigen, that appears in lung cancer cells as they first become cancerous,” Brooks told BioSpace. “LungVax will train the body that the neoantigen is a danger and that this protein is a red flag for cancer. This allows the immune system to recognize the neoantigen as a threat and destroy the cells before the cancer has had time to develop.”

Unlike some therapeutic vaccines, the preventive vaccine could be used alone in those individuals with the highest risk of developing cancer, potentially preventing the disease from occurring and negating the need for treatment. If it proves to be promising, LungVax will be moved into clinical trials. In the U.K. alone, there are 48,500 new cases of lung cancer diagnosed every year.

While preventive vaccines are still early-stage, excitement around cancer vaccines more broadly continues to grow as therapeutic vaccines move through mid- and late-stage clinical development. It will not be long before the potential of this approach is either realized or dealt a blow.

For Merck’s part, Ebbinghaus said the company has seen enough promise in the data from mRNA-4157/V940 that it is already in discussion with Moderna for further clinical programs looking ahead to 2025 and beyond.

https://www.biospace.com/article/could-cancer-vaccines-be-the-next-big-breakthrough-in-immunotherapy-/

Travere’s Filspari Could Lead IgA Nephropathy Market

 Despite having not yet received full approval, Travere Therapeutics’ first-in-class endothelin and angiotensin II receptor antagonist Filspari—which received the FDA's accelerated approval in February 2023—is already making strides in treating IgA nephropathy.

A rare autoimmune disease, IgA nephropathy occurs when immunoglobulin A accumulates in the kidneys, leading to blood and protein in the urine. It affects around 60,000 people in the U.S.

According to the National Kidney Foundation, the four main classes of approved drugs used to treat IgA nephropathy are corticosteroids, immunotherapies, ACE inhibitors and angiotensin II blockers. While corticosteroids and immunotherapies tamp down immune responses, ACE inhibitors decrease angiotensin production by inhibiting angiotensin-converting enzymes, and angiotensin II blockers inhibit the angiotensin II receptor. By decreasing overall angiotensin activity and its downstream effects in the body, ACE inhibitors and angiotensin II blockers reduce hypertension and proteinuria over time via the renin-angiotensin-aldosterone system.

There is ample reason to believe that Filspari is clinically efficacious enough to warrant serious provider consideration compared to traditional treatments. For example, immunotherapies indicated for treating IgA nephropathy, such as cyclophosphamide combined with prednisone, lead to adverse effects ranging from drug-induced hepatitis to widespread systemic infections. When Filspari was approved last year, it was touted as the first and only non-immunosuppressive therapy to reduce proteinuria in IgA nephropathy. The adverse effects caused by immunotherapies are riskier to manage than are Filspari’s adverse effects, which include peripheral edema, hypotension, dizziness, hyperkalemia and anemia.

According to Travere, while traditional ACE inhibitors or angiotensin receptor blockers with no endothelin activity have been used to treat IgA nephropathy, these agents have only been able to delay end stage renal disease by 7.9 years on average when initiated in patients with an estimated glomerular filtration rate that indicates kidney disease.

Meanwhile, angiotensin II receptor antagonists with endothelin inhibition, such as irbesartan or Filspari, can delay end-stage renal disease for longer—by 11.1 years on average for irbesartan and 15.6 years for Filspari. (Irbesartan, brand name Avapro, is a drug chemically similar to Filspari that is approved to treat hypertension and diabetic nephropathy.)

Because the standard of care treatment with traditional ACE inhibitors or angiotensin receptor blockers with endothelin activity provides more effective long-term management of IgA nephropathy than angiotensin II receptor antagonists without endothelin inhibition, drugs with endothelin-inhibiting activity will be favored.

In terms of newer medications on the market, although Calliditas Therapeutics’ systemic steroid Tarpeyo (budesonide) received full approval in December 2023 for IgA nephropathy, it can cause infections if used chronically and does not address the root cause of IgA nephropathy but rather targets the source of IgA antibody production before the IgA autoantibodies end up in the kidney. 

In addition to seeking indication expansions in other renal diseases, such as focal segmental glomerulosclerosis, Travere aims to make Filspari the first-line agent for IgA nephropathy and to push for its use in earlier interventions to maximize nephroprotection.

Because Filspari can be combined with Tarpeyo but not with other angiotensin receptor blockers, future clinical trials may involve examining this combination for IgA nephropathy. With Filspari, Travere is well-positioned to continue expanding its rare disease footprint in the coming years.

https://www.biospace.com/article/opinion-travere-therapeutics-leads-onward-in-iga-nephropathy/

FDA Action Alert: Dynavax, Ascendis and BMS

 May will be relatively slow for the FDA, with only four big target action dates. Among other announcements, the regulator is scheduled to release its verdicts on a hepatitis B vaccine for adults on hemodialysis and two potential indications for BMS's CAR-T therapy Breyanzi. 

Read below for more.

Dynavax Proposes Hepatitis B Vaccine for Patients on Hemodialysis

Today is the day by which the FDA is scheduled to publish its decision on Dynavax Technologies’ sBLA seeking to expand the label of its hepatitis B vaccine Heplisav-B for use in adults on hemodialysis.

Heplisav-B won its initial U.S. approval in 2017 for the prevention of hepatitis B, caused by all known subtypes of the virus, in adults aged 18 years and above. According to its label, Heplisav is a recombinant protein vaccine comprised mainly of the hepatitis B surface antigen, which can prime the body to protect against the virus’ infection.

Heplisav-B is designed to be administered in two doses, and is the only approved hepatitis B shot that completes the vaccination series in one month. The U.K.’s Medicines and Healthcare products Regulatory Agency granted Heplisav-B Marketing Authorization in February 2023.

Dynavax reported that Heplisav-B brought in $213 million in net revenues in 2023, representing a 69% year-over-year increase. As of the end of December 2023, Heplisav-B controlled approximately 42% of the U.S. hepatitis B vaccine market, up from 35% at the end of 2022.

In a statement accompanying the company’s full-year results, CEO Ryan Spencer said that Heplisav-B saw “record revenue growth” in 2023 and became the “market share leader in two largest growth segments.” These achievements will help Dynavax establish Hepliav-B as “the leading vaccine in the U.S. adult hepatitis B vaccine market,” he said.

The company expects continued growth for Heplisav-B in 2024, anchored by the upcoming potential approval. Dynavax forecasts net product revenues of $265 million to $280 million for Heplisav-B this year.

Ascendis Tries Again for Hypoparathyroidism Approval for TransCon PTH

The FDA is scheduled on May 14 to release its verdict on Ascendis Pharma’s resubmission for its investigational drug TransCon PTH (palopegteriparatide), which is being proposed as a treatment for adults with hypoparathyroidism.

Designed to be orally available and formulated to be long-acting, TransConPTH is a prodrug of the parathyroid hormone that works by restoring physiologic levels of the hormone for 24 hours each day. This mechanism of action could potentially allow it to counter hypoparathyroidism, a rare disorder characterized by the insufficiency of parathyroid hormone, in turn leading to low calcium and high phosphate levels.

Patients with hypoparathyroidism experience weakness, muscle cramps and headaches, and the condition can lead to long-term complications such as calcium deposits in the eyes, brain and kidneys. Currently, hypoparathyroidism is managed through high-dose therapy with calcium and active vitamin D, which does not optimally control the condition.

Ascendis first submitted a drug application for TransCon PTH in 2022, which the FDA rejected in May 2023, citing manufacturing concerns. The regulator did not identify problems with the drug’s safety or efficacy, and it did not ask for additional studies.

Currently, TransCon PTH is approved in the U.K. and European Union, where it is marketed under the brand name Yorvipath.

BMS Awaits Two Verdicts for CAR-T Therapy Breyanzi

To close out the month, BMS is looking at two target action dates for its CAR-T therapy Breyanzi (lisocabtagene maraleucel): May 23 for relapsed or refractory follicular lymphoma (FL) and May 31 for relapsed or refractory mantle cell lymphoma (MCL).

In FL, Breyanzi is backed by the Phase II single-arm TRASCEND FL study, which, with 213 enrolled patients, is the largest clinical trial so far to assess a CAR T therapy in relapsed or refractory indolent non-Hodgkin lymphoma, including FL.

BMS presented data from TRANSCEND FL in December 2023, showing that Breyanzi elicited a 95.7% complete response rate in patients with high-risk relapsed or refractory FL when used in the second-line setting. Median progression-free survival had not been reached at the time.

Meanwhile, BMS is backing Breyanzi’s MCL application with findings from the MCL cohort of the TRANSCEND NHL 001 study. Published in December 2023 in the Journal of Clinical Oncology, results from the pivotal Phase I trial demonstrated significant and clinically meaningful treatment responses in heavily pre-treated patients, most of whom achieved a complete response.

Breyanzi is a CAR-T cell therapy that works by targeting the CD19 surface protein, which is commonly expressed on B cells. Once bound to CD19, Breyanzi proliferates, induces the release of proinflammatory cytokines and cell death in cancer cells. The FDA first approved Breyanzi in February 2021 for relapsed or refractory B-cell lymphoma.

In March 2024, Breyanzi picked up two new approvals, one for chronic lymphocytic leukemia and the other for small lymphocytic leukemia.

https://www.biospace.com/article/fda-action-alert-moderna-dynavax-ascendis-and-bms/

Cut or Keep Running? How Companies Respond to Failed Confirmatory Trials

 It’s been a little over a month since Amylyx Pharmaceuticals announced it would withdraw its amyotrophic lateral sclerosis drug Relyvrio from the market after it failed to meet the primary endpoints in a Phase III trial. Relyvrio received approval in 2022 after a positive Phase II study and the company had vowed to pull it if the second trial was not successful.

Relyvrio isn’t the first drug to be withdrawn from the market after additional trials have failed to reaffirm earlier studies supporting the efficacy and safety of novel therapies. Conversely, some drugs stay on the market for years after confirmatory trials don’t deliver the expected results. For example, Jazz Pharmaceuticals and PharmaMar’s Zepzelca remains on the market for small cell lung cancer despite not meeting overall survival endpoints.

Even for drugs that have yet to reach the market, companies can be faced with tough decisions when late-stage trials do not yield the expected results. BrainStorm Cell Therapeutics, for example, continues to develop its cell therapy NurOwn for ALS even after a Phase III trial failed to meet its primary endpoint and an FDA advisory committee voted against approval last year.

Market withdrawal and pipeline decisions after late-stage failures depend on a number of factors, including the details of the study’s data. “The first thing that comes to mind is, why did the trial fail? Is it related to efficacy, safety, or both?” Nicolas Schmitz, a senior market analyst at KBI Biopharma, told BioSpace in an email. “The nature of the failure (statistical significance, side effects or patient recruitment challenges) will obviously play a crucial role in the future of the drug candidate and the company that owns it.”

Not Cut and Dry

In the last few years, there have been a handful of approved drugs withdrawn from the market. TG Therapeutics received accelerated approval for Ukoniq in February 2021 but voluntarily withdrew the lymphoma drug in 2022 after updated data showed a possible increased risk of death. Gilead Sciences’ Zydelig for lymphoma and small lymphocytic leukemia received accelerated approval in 2014 but was voluntarily withdrawn in 2022 after enrollment challenges hindered its confirmatory trial. And Genentech’s Tecentriq won accelerated approval in 2016 for urothelial carcinoma but failed to meet its overall survival endpoint in a Phase III trial the following year for patients with locally advanced or metastatic urothelial cancer who had been treated with platinum chemotherapy. It was withdrawn from the market in 2021 for this indication, with additional indications being pulled in 2022.

Failed trials play a key role in earlier development decisions too. For example, a failed Phase III study can cause some companies to shutter entire development programs, while others will continue pushing forward with additional studies, perhaps with different trial designs or targeting different patient populations.

In September 2023, when the FDA’s Cellular, Tissue and Gene Therapies advisory committee voted 17-1 against recommending NurOwn for approval, the company decided to continue developing the therapy.

“We’re heartened and encouraged by the support of the community, but it really comes back to the evidence that we have which drives us,” Co-CEO Stacy Lindborg told BioSpace.

The advisory committee had been critical of the company’s manufacturing plan and questioned the greater mortality rate in the experimental group. Moreover, the primary endpoint of BrainStorm’s Phase III trial—the proportion of participants experiencing an improvement of 1.25 points per month post-treatment on the ALSFRS-R vs. placebo—did not meet statistical significance. However, this endpoint was achieved in a subset of patients.

“At face value, we took the endpoints, and our first inclination was that this is a failed trial,” Lindborg said, adding that all companies have a responsibility to trial participants to understand what they have learned. “When we started seeing that the cells had done what we expected, we started to ask additional questions.” Indeed, the team saw in the trial data improvements in neurofilament light and other markers of neurodegenerative disease, Lindborg said. BrainStorm came to an agreement with the FDA on the design of a Phase IIIb trial for NurOwn in February 2024. Lindborg is optimistic that the trial will succeed, but would not comment on what action the company would take if the new endpoints are not met.

Sarepta Therapeutics is also looking to move forward with a therapy that hasn’t delivered as expected in clinical trials. The FDA accepted Sarepta’s supplemental Biologics License Application (sBLA) for full approval and to expand the label of its Duchenne muscular dystrophy gene therapy Elevidys earlier this year, despite its failing a confirmatory trial in October 2023. The company expects a decision on or before June 21.

Financial Factors

Finances also play a role in whether companies pursue additional trials in the face of less-than-ideal results. A larger company might have more freedom to pursue further development following a failure than a small company would. Schmitz pointed to Eli Lilly’s solanezumab, which failed to meet endpoints in multiple trials before being dropped in 2023, as an example. Lilly earned more than $34 billion in revenue in 2023, with 63% of that coming from a handful of drugs. In comparison, Amylyx earned $380 million in revenue in 2023, with Relyvrio its only marketed product.

If a company is “struggling with cash” with no alternative products, a failed trial “might certainly be the end of the adventure” for that company, he said.

“The key tenets of every product are cycle time, cost and value,” Lindborg said. “Is there an appropriate need, such that what you’re investing can be recouped and that you’re able to continue to do research in the future?”

Companies may also sell drug programs that failed in clinical trials to companies with the resources to continue research and development, Schmitz said. Lindborg added that partnerships between companies could help cost-effectiveness and efficiency by sharing capacity and headcount across organizations.

Whether or not a drug is withdrawn from the market or development is halted ultimately affects whether trial participants and other patients can access that drug. A study examining cancer drugs that failed clinical trials after receiving accelerated approval found that multiple drugs were still recommended by the National Comprehensive Cancer Network even after negative results were available.

Amylyx will continue to make Relyvrio available for free to patients who believe the drug is helping them, a decision that was commended by The ALS Association, according to The Washington Post.

“We try to boil every question down to, what’s best for people with the disease, what’s best for the families, what’s best for the community,” Amylyx Co-CEO Justin Klee told BioSpace last month. “We ran a large, randomized control trial. It was a very well-done trial, and the benefit was uncertain.”

https://www.biospace.com/article/cut-or-keep-running/