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Explore the latest pharmaceutical validation developments with industry experts from Barry-Wehmiller Design Group, Kneat Solutions, and No Deviation. You’ll gain valuable data-driven insights and discover emerging trends from the State of Validation 2024 industry report that are shaping the validation landscape. 


Recent Developments in Pharmaceutical Validation

Webinar Date/Time: Thu, Sep 12, 2024 11:00 AM EDT

Advancing Validation: 2024 Insights and Trends

AbbVie Pedro Valencia ADCs

PE: How is AbbVie using novel cancer biomarkers to develop potential first-in-class ADCs for the treatment of advanced solid tumors?

We're constantly looking for biomarkers that can help us to do two key things. The first is to tackle cancer cells. and spare normal cells. We’re looking for specific antigens that are over-expressing tumor cells, and you see limited expression in normal cells. We want to make sure that target that’s over-expressed is critical for the survival of the cancer cell. Once you block it, you can actually drive a cancer cell death. That’s what we're looking for. In that perspective, c-Met is one of those biomarkers that is over expressing multiple tumor types such as lung, colorectal, gastric, and other GA tumors. We as an industry have tried to tackle c-Met in the past but have been unsuccessful. It would actually be successful to tackle what we call met, which is a gene inside the cell.

There’s this thing called met amplification, where the cancer cell produces multiple copies of the gene, and around 30% of patients have it. We can actually tackle that with small molecules. But once the gene becomes a protein and gets over-expressed in the cell, that over-expression is something we haven’t been able to target. For example, we know that on lung cancer, c-Met over-expression is about 25% to 50% in colorectal cancer, and it could be anywhere from 30% to 70% depending how you measure it, so it’s quite prevalent.

With ADCs, we’re trying to tackle c-Met over-expression on the surface of cancer cells. That was novel, and we can do it through ADCs. 706 has a target called SEZ6, and it’s a target that is over expressed in neuroendocrine cells or neuroendocrine neoplasms. When you think about it, multiple tumor types kind of have a subset of cells that are neuroendocrine driven. Small cell lung cancer is one of the few that has everything driven by neuroendocrine cells. The beauty of SEZ6 is over-expressing those cells and limited expression in normal cells. So, we can tackle it with an ADC and drive the results that we're seeing today.

PE: ADCs have redefined the treatment of cancer in recent years. Can you please discuss the promise of this emerging class and what the future may hold?

At the end of the day, ADCs work like a trojan horse. You have a good antibody that cancer cells are happy to receive, but once you hook into the cancer cell receptor, you deliver the payload, which is pretty much chemotherapy. It’s actually a highly potent version of the regular chemotherapy cancer patients are given on a regular basis. So, from that perspective, our goal is to replace chemotherapy. Our grand goal with ADCs is to replace good old, decades old chemotherapy that is really toxic for some patients. That’s how we see the redefinition of cancer treatment in the future with ADCs. So, what do we see in the future? Well, if you think about it, chemotherapy is being given in combination with other agents. In the future, we see ADCs being given in combination with chemotherapy. There will be one with other agents such as immuno-oncology agents. So, if you combine the ADC and the PD1s, you can start seeing that synergy come together and kind of start really dreaming about cures for the patients. All in all, we're super excited about ADCs replacing chemotherapy. 

In an interview with Pharm Exec Associate Editor Don Tracy, Pedro Valencia, VP, Solid Tumor Pipeline Strategy & Execution, AbbVie, discusses using novel cancer biomarkers to develop potential first-in-class antibody drug conjugates (ADCs) and the promise that they offer. 

Utilizing Biomarkers to Develop First-in-Class Antibody Drug Conjugates to Treat Advanced Solid Tumors

FDA PD-1 Inhibitor Challenge

PE: What are the legal implications of the FDA challenging the broad labeling of PD-1 inhibitors for gastric cancers?

It's definitely going to limit the number of patients who qualify for the treatment. I think because of this limiting factor, it's going to open up the industry to lawsuits. I think the lawsuits are going to likely be from patients or providers who believe that they're being denied access to necessary treatment based on these new, more restrictive labeling criteria that we're seeing.

PE: How does this FDA action affect pharmaceutical companies from a regulatory and compliance standpoint?

What that means is that only patients with a certain level of PDL-1 expression would be able to be eligible for the treatment for these inhibitors in gastric cancer. Again, I think when you look at the whole aspect of what this means, it's going to mean excluding a large portion of patients from the treatment.

The FDA’s recent challenges to the broad labeling of PD-1 inhibitors for gastric cancers, particularly around PD-L1 expression, could have far-reaching legal, regulatory, and strategic implications for pharmaceutical companies and healthcare providers. This shift could significantly restrict patient access to these treatments by mandating a threshold for PD-L1 expression, which is anticipated to exclude a large portion of patients, particularly those with low PD-L1 expression levels. These patients, lacking alternative treatment options, may initiate litigation, claiming denial of necessary treatment.

From a regulatory standpoint, companies will need to revise labeling to specify PD-L1 thresholds, impacting compliance procedures and possibly requiring additional studies. This narrowing of indications is also likely to increase the cost of these therapies, potentially limiting their inclusion in insurance formularies and intensifying market access challenges. Consequently, insurers might also face legal scrutiny from patients and providers who feel that access is unfairly limited due to the new labeling standards. Moreover, product liability claims could arise if adverse events occur under a broader indication, adding further risk.

Pharmaceutical companies may argue that biomarkers can restrict access, which could touch on genetic discrimination concerns, though the Genetic Information Nondiscrimination Act (GINA) may limit this defense’s applicability. This labeling challenge could also impact future drug development strategies, as companies may become more cautious about targeting treatments based on specific biomarkers. The FDA’s stance may deter innovation by slowing research and development (R&D) timelines, as companies may hesitate to invest in drugs with narrow patient populations. This situation may also rekindle debate around Right to Try laws, which aim to broaden treatment access for critically ill patients. Overall, the FDA’s challenge is poised to reshape market dynamics and legal risks, creating a complex landscape for manufacturers and healthcare providers alike.

Ron Lanton, Partner, Lanton Law, discusses the legal implications of the FDA’s broad label challenge to PD-1 inhibitors for gastric cancers.

FDA Challenges to Broad Label Laws for PD-1 Inhibitors

PD-1 restrictions

PE: Can you explain the FDA’s reasoning behind targeting the broad labeling of PD-1 inhibitors and how this might impact future drug approvals in oncology?

I think the change in labeling is going to push both providers and patients to file challenges, because, again, that access to treatment, I think it's already opened the door to product liability issues. I have a quote from the FDA that says ‘If patients with low or no PD-1 expressions are not expected to benefit based on the available data, then administering anti-PD1 therapy has the potential for harm, including serious immune related adverse events on top of a maladency that could markedly affect a patient's quality of life.’ After looking at that, I think either way, manufacturers and insurance companies are going to be sued on access either to the treatment because the narrow language to label or because of possible adverse effects allowed under a broader label.

 The FDA’s recent challenges to the broad labeling of PD-1 inhibitors for gastric cancers, particularly around PD-L1 expression, could have far-reaching legal, regulatory, and strategic implications for pharmaceutical companies and healthcare providers. This shift could significantly restrict patient access to these treatments by mandating a threshold for PD-L1 expression, which is anticipated to exclude a large portion of patients, particularly those with low PD-L1 expression levels. These patients, lacking alternative treatment options, may initiate litigation, claiming denial of necessary treatment.

Ron Lanton, Partner, Lanton Law, discusses why the regulatory body made the decision to place restrictions on PD-1 inhibitors for gastric cancers. 

Rationale Behind the Recent FDA PD-1 Inhibitor Label Restrictions

Future Studies

PE: How might this labeling challenge influence future drug development strategies, especially in terms of targeting specific cancer subtypes or biomarkers in gastric cancers?

I think it’s going to slow down R&D altogether, that’s the first thing. I think these restrictions that were noted by scores that were cut off below a 10. I think Merck says something about that's going to exclude about 65% of new patients with HER2-negative stomach cancer. Additionally, this is going to also make it so that the drug is more expensive than it already is, and that's definitely going to affect future access to insurance formularies that are going to restrict access. I know we've talked before about DVMs and how they view price and how all that comes, to how they think about things and what they put on their formulary. So, this is definitely going to be an external factor to that.

Ron Lanton, Partner, Lanton Law, ways that the recent FDA PD-1 inhibitor label restrictions could influence future drug development strategies.  

The Influence of PD-1 Inhibitor Label Restrictions on Future Studies

Legal Action PD-1 Inhibitor

PE: What legal defenses or strategies might companies consider arguing in favor of keeping broader indications for their PD-1 inhibitors in gastric cancers?

I think that many providers have said that limiting the use of PD-1 inhibitors in gastric cancer is not going to help anybody. I think that one legal defense that could be used is that biomarkers limit access, maybe based on a genetic discrimination claim, which I haven’t seen in a couple of years. That’s kind of died off from what I’ve seen. It’s still there, but it’s not in the news the way it used to be. But to continue on this thought, I think the use of biomarkers is key in clinical studies. I think that a lot of people are afraid that using them in such a strict manner is going to undermine a lot of the clinical studies and limit access for patients who have been accepted under the Right to Try laws. It’s a volatile topic, but it’s definitely going to come back to the forefront with something like this.

Ron Lanton, Partner, Lanton Law, discusses potential challenges that will come as a result of the FDA’s recent move to tighten label restrictions on PD-1 inhibitors for gastric cancers. 

Potential Legal Action Against PD-1 Inhibitor Label Restrictions for Gastric Cancers

The FDA has approved a label expansion for Roche’s Pathway anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody test. According to the company, this is the first FDA-approved companion diagnostic for identifying HER2-positive biliary tract cancer (BTC) patients eligible for treatment with Jazz Pharmaceuticals' Ziihera (zanidatamab-hrii). Additionally, Ziihera is he first FDA-approved treatment for adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC.

"This test is a step forward in furthering access to personalized medicine," said Jill German, head, pathology lab, Roche Diagnostics, in a press release. "The prognosis for patients diagnosed with BTC is poor, as very few treatment options exist. Now, these patients have access to the first standardized test that could make them eligible for targeted therapy, potentially improving clinical outcomes."

According to Roche, the Pathway anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody delivers timely, clear and reliable results, enabling therapeutic decisions that can lead to better outcomes for patients. Currently, the antibody is indicated as an aid to identify breast cancer patients eligible for HER2-targeted treatment with Herceptin, Kadcyla, and Enhertu. Further, it is used in combination with the fully automated Ventana BenchMark slide staining instrument. Roche states that it standardizes all immunohistochemistry (IHC) processes from baking through staining and reduces the possibility of human error and minimizes inherent variability resulting from individual reagent dilution and other processes found in manual and semi-automated IHC methods.

BTC comprises 3% of gastrointestinal cancers in the United States, with most cases diagnosed at advanced stages and a five-year survival rate as low as 3% for metastatic disease and 19% for disease that is localized to the original tumor site.1 According to the American Cancer Society, 8,000 people in the United States are diagnosed with bile duct cancer on an annual basis, including both inside and outside the liver. Despite these confirmed numbers, it is possible that numbers could be higher due to the cancers being difficult to detect. While it is mainly found in older people, younger people can experience it as well. The average age of people in the US diagnosed with bile duct cancer is in the 70s.

According to the National Cancer Institute, there have been around 41,630 cases of bile duct cancer confirmed this year, representing 2.1% of all cancer cases. This has resulted in 29,840 deaths, representing 4.9% of all cancer related deaths this year. Additionally, the rate of new cases was 9.4 per 100,000 men and women per year. In the United States, approximately 1.1% of men and women will be diagnosed with liver and intrahepatic bile duct cancer at some point during their lifetime, based on 2018–2021 data, excluding 2020 due to COVID-19.

Nearly all bile duct cancers are cholangiocarcinomas, which are a type of adenocarcinomas. Other less common forms include sarcomas, lymphomas, and small cell cancers. Additionally, hepatocellular carcinoma is the most common type of cancer that starts in the liver.

1. Roche receives FDA approval for first companion diagnostic to identify patients with biliary tract cancer eligible for HER2-targeted treatment with ZIIHERA. 

November 25, 2024. Accessed November 25, 2024. https://www.prnewswire.com/news-releases/roche-receives-fda-approval-for-first-companion-diagnostic-to-identify-patients-with-biliary-tract-cancer-eligible-for-her2-targeted-treatment-with-ziihera-302314548.html

Accessed November 25, 2024. https://www.cancer.org/cancer/types/bile-duct-cancer/about/key-statistics.html

3. Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. 

Accessed November 25, 2024. https://seer.cancer.gov/statfacts/html/livibd.html

Accessed November 25, 2024. https://www.cancer.org/cancer/types/bile-duct-cancer/about/what-is-bile-duct-cancer.html

Pathway is now the first and only FDA-approved companion diagnostic for identifying HER2-positive biliary tract cancer patients eligible for treatment with Ziihera. 

Kneat

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