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Precision Medicine in 2023: Gene Therapies Take Center Stage Amid Regulatory, Pricing Debates


NEW YORK – 2023 was undoubtedly the year of the gene therapy in precision medicine.

The US Food and Drug Administration last year approved several gene therapies that for the first time promise to treat, and even cure, rare, inherited diseases of the blood, skin, and muscles. "The greater move into rare disease last year meant progress for precision medicine beyond cancer," said Susanne Munksted, chief precision medicine officer at Diaceutics, a diagnostics data analytics firm that also advises life sciences companies on personalized medicine development strategies. Munksted estimated that 25 percent of Diaceutics' consulting work with clients last year was in indications outside of oncology.

While more precision medicines entered the market in diverse disease settings, the multimillion-dollar price tags attached to some of these treatments raised concerns across the healthcare sector about the extent to which these medical and scientific feats will be truly accessible to the very patients they are meant to help. Although drugmakers maintain that the benefits of increasingly individualized therapies justify their steep prices, government and commercial payors increasingly want pharma to prove it within coverage with evidence development and risk-sharing schemes, especially as more precision medicines are expected to proliferate for more common conditions like Alzheimer's and heart disease.

Still, drug pricing has always been a fraught topic in the US, and when the government began negotiating prices for the most expensive Medicare drugs this fall, the pharmaceutical industry pushed back that this would limit their ability to recoup development costs and hinder investment in precision medicines for cancer and rare diseases. The argument, while not new, may strike a chord with the public at a time when demand for the latest medical advances like radiopharmaceuticals and CAR T-cell therapies are so high that drug companies are struggling to make enough (see here and here).

But before patients can get precision medicines, they need access to the right tests. Diaceutics' analysis, however, suggests that 50 percent of patients aren't getting optimal treatments due to barriers in the testing ecosystem, including reimbursement. In 2023, states continued to enact bills aimed at improving commercial payor coverage of biomarker tests, though payors have found a lot to dislike in these laws, and it remains to be seen if they will actually enable more patients to get appropriate care as intended.

Amid these ongoing issues, a bevy of new individualized drugs came to market in 2023.

By Precision Medicine Online's count, the FDA approved 28 precision therapy indications. Of these, 17 were for treating cancer and 11 were for other diseases, including five gene therapies. While 2022 was a banner year for CAR T-cell therapies, accounting for six of the 21 precision oncology approvals, the FDA didn't add to this list in 2023. (Editor's note: With the launch of Precision Medicine Online in 2023, we expanded our coverage beyond cancer to all conditions. As such, we aren't providing a year-over-year comparison of the total approved precision medicines.)

Quick Stats

A year of firsts

In the gene therapy space, 2023 was a year of many firsts. The agency closed the year with the simultaneous approval of two cell-based gene therapies, Vertex Pharmaceuticals' Casgevy (exagamglogene autotemcel) and Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel), for patients with sickle cell disease who have a history of painful episodes, called vaso-occlusive crises. While both firms hope longer-term data will prove these drugs to be one-time curative treatments, Casgevy is the first to use the CRISPR-Cas9 gene editing system to disable the BCL11A gene and enable production of fetal hemoglobin to compensate for a defective adult version in sickle cell patients.

Other advances in the space included Krystal Biotech's Vyjuvek (beremagene geperpavec), the first FDA-approved topical gene therapy for treating wounds in patients with dystrophic epidermolysis bullosa due to COL7A1 mutations; Sarepta Therapeutics' Elevidys (delandistrogene moxeparvovec), the first gene therapy for Duchenne muscular dystrophy (DMD); and BioMarin's Roctavian (valoctocogene roxaparvovec), the first gene therapy for adults with severe hemophilia A.

To ensure these advances continue in the rare disease space, leaders at the FDA talked a lot last year about shepherding more gene therapies through the accelerated approval pathway; launched a program to pilot strategies for expediting promising treatments through the regulatory process; and supported the Bespoke Gene Therapy Consortium, which wants to create a playbook for developing adeno-associated virus-based gene therapies across eight rare disease settings.

These advances solidified 2023 as "the year of gene therapy and rare disease" for Diaceutics' Munksted.

Other notable precision medicine approvals outside of the gene therapy space came in April with the approval of Biogen's Qalsody (tofersen), an antisense oligonucleotide for patients with SOD1-mutated amyotrophic lateral sclerosis. Earlier in the year, Eisai's Leqembi (lecanemab) became the second FDA-approved Alzheimer's drug that targets beta-amyloid, a biomarker that is still widely thought to play a key role in the pathophysiology of the mind-robbing disease, but plenty of experts now also question whether removing beta-amyloid plaques can improve or prevent loss of memory.

While Leqembi doesn't improve patients' cognitive abilities, the agency converted its accelerated approval into a full approval within seven months based on data showing that it modestly slowed cognitive decline compared to placebo. But there's still a lot of uncertainty around how meaningful this is for patients' daily functioning, especially since the drug can cause brain swelling and bleeding in some patients.

In precision oncology, while most of the approvals last year occurred for drugs that target well-known biomarkers such as BRCA1/2, BRAF, and NTRK alterations, Munksted highlighted that some new biomarkers did emerge. For example, Menarini's selective estrogen receptor degrader Orserdu (elacestrant) was approved for certain advanced breast cancer patients with ESR1 mutations.

In blood cancer, Daiichi Sankyo's FLT3 inhibitor Vanflyta (quizartinib) became a new option for acute myeloid leukemia patients who are newly diagnosed and have FLT3-internal tandem duplication mutations. Vanflyta, which must be combined with standard induction and consolidation chemo and then given on its own as maintenance therapy, is an example of precision medicines moving into earlier lines of care. Given that a lot of cancer patients still only get precision medicines for advanced disease and only after chemotherapy, "moving this up in the patient's treatment trajectory is a positive sign."

Meanwhile, in the CAR-T space, the agency issued a safety warning in November that patients receiving such treatments targeting the B-cell maturation antigen and CD19 may be at higher risk of developing new T-cell malignancies. However, given that the agency issued this warning based on 20 reports of T-cell malignancies and CAR T-cell therapies have been administered more than 30,000 times to date, Mikkael Sekeres, professor of medicine in the division of hematology at the University of Miami's Sylvester Comprehensive Cancer Center, estimated that this presents around a one-in-a-thousand risk that a CAR T-cell-treated patient will develop a new cancer.

There's always been a theoretical risk of T-cell malignancies with these therapies, Sekeres noted, since they involve reengineering the immune system, and T-cell malignancies arise from the immune system. On the other hand, CAR T-cell therapies have broadly shown to bring about remissions, at least initially, in the majority of patients. "This really boils down to a risk-benefit analysis," he said, noting that while the cancers reported to the FDA are real, "in the relative balance of safety and efficacy … it still wildly favors CAR T."

He has heard anecdotally from other doctors that the FDA's safety warning is making some patients more hesitant to take CAR T-cell therapies, but Sekeres noted that the agency is just doing its job by "flagging this safety signal and making sure it's not worse than what they're seeing."

Committed to LDT regulation

The biggest regulatory news in 2023 was the FDA's proposed rule on oversight of lab-developed tests, which stands to impact the precision medicine space given the critical role diagnostics, particularly LDTs, play in directing therapy. The FDA this fall started down the rulemaking path only after failing to secure a legislative solution in 2022 through the passage of the Verifying Accurate Leading-edge In Vitro Clinical Tests Development (VALID) Act.

The agency's initial regulatory plans for LDTs in the proposed rule have been pilloried widely by labs as something that will drive further consolidation in the industry, hurt small players, and quash innovation. There are also plenty of stakeholders in the healthcare sector who feel that LDTs need more stringent oversight in the interest of patient safety. Despite receiving more than 6,700 public comments on the controversial proposed rule, the agency remains focused on finalizing it by April 2024.

Wendy Rubinstein, a senior scientific officer within the National Cancer Institute's cancer prevention division, who until last year was the director of personalized medicine within the FDA's device division, felt that VALID offered the clearest path for FDA regulation of LDTs, but in its absence, the fact that the agency proposed rulemaking "is evidence of their commitment to continuing on this path."

Still, the FDA has been trying to regulate LDTs for several decades now, only to be stymied by industry pushback. Even though the agency has repeatedly stated that more oversight is needed because it has received reports of faulty LDTs harming patients, stakeholders have demanded proof of these harms and have been dissatisfied with the examples the agency has provided.

"It's a chicken and an egg problem," Rubinstein said, since under the present oversight system under CLIA, labs aren't required to report harms associated with their tests in the way they would have to under the FDA. While at the FDA, Rubinstein was involved in the 2022 safety communication warning people that genetic noninvasive prenatal screening (NIPS) tests can provide false results and need diagnostic confirmation. By monitoring Reddit chats, the agency identified patients who were experiencing a lot of anxiety and making decisions about whether to proceed with their pregnancies based on false NIPS results, she said, adding that without systems for systematically tracking LDT-related adverse events, it's difficult to determine how pervasive the problems are.

Howard McLeod, director of Utah Tech University's Center for Precision & Functional Genomics, on the other hand, believes that the FDA has yet to have an honest discussion with stakeholders about LDT regulation. In his view, the agency has put forth "weak case examples" of harm and proposed "insufficient remedies." 

"Stop thinking that the world of laboratory medicine, where there are stable analytics for a small number of analytes in large numbers of patients, is the same as the world of precision medicine, where new knowledge needs to become clinically actionable as soon as possible," he said. Instead of focusing on approving or clearing a platform, McLeod believes the FDA's Center for Devices and Radiological Health should be moving toward credentialing specific genes or variants and putting out clear guidance on how new information can be incorporated into tests quickly. "I don't see another area of CDRH's portfolio where 'approval quickly' equates with out-of-date," McLeod said.

In precision oncology, doctors may choose to order LDTs that gauge more up-to-date panels of therapeutically actionable biomarkers than FDA-approved companion tests that need to go through the agency to add new biomarkers. The agency certainly seemed cognizant of this reality when it launched a pilot program last year to bring more transparency around the performance characteristics of LDTs used to identify best responders to cancer therapies. In this program, the FDA proposes to review and publicly post data on the analytical performance characteristics of assays drugmakers used to enroll cancer patients in trials that support approval of their therapies.

The idea is that these publicly available minimum performance characteristics can be a benchmark for other firms testing the same biomarkers on LDTs without FDA approval. "The one drug-one [companion] test model is pretty unwieldy and leaky because of all the follow-on [lab] tests that come on" the market, said Rubinstein. "The FDA realizes that something has to happen, and they've chosen, rightly, to focus on transparency."

Munksted characterized the pilot as a "good idea" in theory but remains uncertain how willing drug and diagnostics companies will be to volunteer performance characteristics on their tests. "I'm really curious to see how that evolves," she said.

Emerging diagnostics

For the time being, though, LDT developers remain free to market tests through the CLIA pathway without FDA approval or clearance while they evaluate and fine-tune the performance of their tests. In 2023, healthcare providers continued to express concern about the market rollout of multi-cancer early detection tests, or MCEDs, before their performance and clinical impact are fully understood.

For example, since launching the Galleri test in 2021, Grail has been providing employees of healthcare organizations early access within pilot programs and collecting real-world evidence on its test. Last year, Grail inked such arrangements with the commercial health plan Point32Health, the regional healthcare system Intermountain, and the Department of Veterans Affairs.

In the fall, Grail provided further insights from the prospective PATHFINDER study on what additional diagnostic workups are needed when Galleri detects an early cancer signal. The study, involving more than 6,600 participants, found a cancer signal in 92 individuals, and 35 of these results turned out to be true positives and 57 were false positives. The majority of patients with both true and false positives needed more lab tests and imaging to follow up on the Galleri signal, but few underwent surgery.

To Munksted, the data presented to date on MCEDs suggest that while promising, the test is "not ready for prime time." The NCI, too, is reserving judgment on whether these tests can reliably detect cancer "early" and is calling them just multi-cancer detection tests, or MCDs.

"The NCI would like to wait until there's more data before we are promoting this in any way," said Rubinstein. While it is encouraging that prospective data is emerging on these tests, there are many unanswered questions, she said, such as the number of follow-up tests needed to get to a diagnostic resolution after a positive signal and the utility of whole-body imaging.

The NCI is planning to learn more about these tests' performance and impact within the Vanguard study slated to launch in 2024. The NCI has had "a tremendous response" from interested assay developers, Rubinstein said, including from companies developing tests that aren't circulating tumor DNA-based. While Vanguard is a feasibility study and its aim isn't to find the best-performing test, it will inform the design of a later randomized-controlled trial that will assess whether these tests improve mortality compared to a control arm as a primary endpoint. "We think that's what matters," Rubinstein said.

Outside of early cancer detection, liquid biopsies are starting to show promise in monitoring cancer progression following treatment by assessing minimal residual disease (MRD). At the American Society of Hematology's annual meeting in December, researchers presented studies in which they used MRD assessments to predict progression earlier than imaging in patients with aggressive B-cell lymphomas and determine more accurately which newly diagnosed lymphoma patients need more intense first-line treatment.

Julie Vose, chief of the division of hematology and oncology at the University of Nebraska Medical Center, expects the use of MRD testing will continue to grow. Since 2018, Amgen's bispecific T-cell engager Blincyto (blinatumomab) has been available for treating acute lymphoblastic leukemia patients who are in remission but MRD-positive. That same year, the FDA approved Adaptive Biotechnologies' ClonoSeq assay for detecting and monitoring MRD in ALL and multiple myeloma patients. 

Outside of the FDA-approved uses of MRD, "what to do with the information [from such tests] is a little bit up in the air," said Vose. For now, doctors at UNMC are mostly following patients who are MRD-positive after treatment more closely with imaging and exams but not giving further treatment until they know for sure that patients have documented disease. In settings where MRD is more established, physicians may choose to act on the results differently, Vose acknowledged, but for now, the impact of modifying treatment based on MRD, as well as more sensitive MRD testing techniques, are being evaluated in many clinical trials.

At ASH, researchers also shared data on a machine-learning model's ability to better predict relapse and survival in patients with acute myeloid leukemia than a standard risk classification tool. In another study, an artificial intelligence model distinguished essential thrombocythemia from prefibrotic primary myelofibrosis, which is associated with poorer outcomes, with 92 percent accuracy. Sekeres flagged this latter study as the first demonstration of AI's ability to do this type of diagnosis. "We're not there yet, but the incorporation of AI in the diagnosis of hematological cancers is an emerging area," he said.

AI and digital pathology are going to expand, Munksted agreed, especially with the emergence of HER2-low and -ultralow as new biomarker considerations for directing HER2-targeted therapies.

The FDA last year approved AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) for patients with metastatic breast cancer who have low HER2-expressing tumors, defined by an immunohistochemistry score of 1+ or IHC 2+ without gene amplification by in situ hybridization. However, there isn't consensus around how much HER2 expression is needed for patients to be considered HER2-low or HER2-negative, and studies have shown variability in pathologists' HER2-low scoring.

These challenges suggest that "we may be getting to the limit of what's humanly reasonable to do with a microscope … [and] has kicked off a number of AI initiatives in the clinical setting," Munksted said. "It will be interesting to follow how that's going to change pathology."

Economics of precision

Alongside a steady stream of new precision drugs and tests, in 2023, there were weekly announcements of layoffs and restructurings across the life sciences sector. Among large drugmakers in the precision medicine space, for example, Biogen announced in July it would cut 1,000 jobs as it prepared to launch Leqembi, which it is co-promoting with Eisai. Numerous smaller players like Sangamo Therapeutics, 2seventy Bio, and Mustang Bio had to make hard decisions about which pipeline projects to invest in. In the diagnostics sector, multiple companies providing next-generation sequencing-based tests and platforms used to guide treatment strategies cut staff, including Roche subsidiary Foundation Medicine, Illumina, Thermo Fisher Scientific, and Natera.

Despite economic pressures, there were several acquisitions in the precision medicine space, for example, Pfizer's purchase of Seagen for its anti-HER2 therapy Tukysa (tucatinib) in a deal with a $43 billion total enterprise value; Bristol Myers Squibb's acquisition of Mirati Therapeutics and its KRAS inhibitor Krazati (adagrasib) in a $4.8 billion deal; AstraZeneca scooping up Gracell Biotechnologies' CAR T-cell therapy in a $1.2 billion deal; and Merck buying Caraway Therapeutics' precision neurodegenerative and rare disease drugs for $610 million. There was a fair bit of activity in the radiopharmaceutical space, notably BMS's acquisition of RayzeBio in a $4.1 billion deal and Eli Lilly's $1.4 billion acquisition of Point Biopharma.

EQRx's ambitions to develop and sell lower-priced "fast follower" cancer drugs, including precision oncology products, didn't pan out after US regulators demanded the company test the activity of the agents in trials in multiple countries, not primarily in China. In August, Revolution Medicines announced it would acquire EQRx in an all-stock transaction worth more than $1 billion and eliminate its entire R&D program.

The EQRx story played out during a year in which drug pricing got a lot of attention. As soon as the US Centers for Medicare & Medicaid Services began negotiating drug prices for the 10 most expensive drugs this fall, as stipulated by the Inflation Reduction Act, pharmaceutical companies sued the government to stop implementation. They maintain that the IRA's price negotiation provisions run counter to the Orphan Drug Act, which incentivizes development of treatments for diseases that affect fewer than 200,000 people. Under the IRA, drugs approved in a single orphan indication are exempt from price negotiations but not if they're approved in multiple indications. 

A lot of precision medicines fall into this category, such as AstraZeneca's PARP inhibitor Lynparza (olaparib), in that they have been approved for multiple orphan and non-orphan indications. Drugmakers opposed to price negotiations argue that the IRA's stipulation in this regard will hinder their ability to advance precision medicines for cancer and rare diseases. 

Despite industry pushback against the IRA, drugmakers will continue to face greater pressure from payors to prove that their pricey precision drugs are helping patients live longer and better. Amid controversy around the extent to which anti-amyloid drugs will actually improve the clinical symptoms of Alzheimer's patients, Eisai priced Leqembi at $26,500 per year, lower than the $28,000 per year price Biogen set for Aduhelm (aducanumab) after facing criticism for an initial $56,000 per year price. Following Leqembi's full approval from the FDA in July, CMS said it would cover it for eligible Medicare patients as long doctors submit data on the drug's efficacy and safety within registries.

The multimillion-dollar cost of the new sickle cell gene therapies has also raised concerns since most patients with this disease tend to be on Medicaid. Bluebird Bio tried to manage messaging around the $3.1 million cost of Lyfgenia soon after its approval in December by announcing an outcomes-based agreement with an unnamed payor. Vertex has suggested that it may also pursue flexible arrangements with payors and offer rebates for patients who don't benefit from Casgevy, which has a $2.2 million price tag.

In McLeod's view, it would help to have a better sense of how these advances stand to impact the total cost of care over a near-term horizon. "What is the value over 12 months or 24 months? There may be even more value over time, but we are suffering from lack of clarity around near-term financial risk," he said. "Amazing science is becoming treatments, and clarity will expedite its place in patient care."

UNMC's Vose said that while the high cost of precision medicines does limit patients' ability to access them, institutions can't be expected to bear that cost. "Institutions have to have approval through the insurance company … because they can't lose millions of dollars," she said. "They couldn't take care of other patients that way."

Vose also understands that drug companies need to recoup the investment they've made in developing these drugs, and as a practitioner, she didn't offer any thoughts on how to address the drug pricing conundrum but only acknowledged the difficult reality. "It is a big problem because it does create disparities. Patients that could benefit from these treatments aren't going to be able to get them," Vose said. "Unfortunately, it's something we have to deal with every day."