An independent committee that advises the FDA on cancer drugs has weighed in on medicines from Spectrum Pharmaceuticals and Oncopeptides, issuing negative votes on both.

First up was Spectrum’s poziotinib, which was developed to treat advanced non-small cell lung cancer (NSCLC) characterized by HER2 exon 20 insertion mutations, a rare genetic signature that drives an estimated 2% to 4% of NSCLC cases.

FDA staff flagged safety concerns at the proposed dose 16 mg dose. In clinical testing, 57% of patients experienced dose reductions and 85% of patients had grade 3 or grade 4 adverse events. They also noted that Boston-based Spectrum is seeking accelerated approval at that once-daily 16 mg dose, but the planned confirmatory study will be at 8 mg twice daily. Last Thursday, the committee voted 9 to 4 that the therapy’s benefits do not outweigh its risks. An FDA decision for the drug is due by Nov. 24.

Following Spectrum, Oncopeptides faced the advisory committee regarding its multiple myeloma drug, Pepaxto. The FDA awarded Pepaxto accelerated approval last year, but months later issued an alert that noted a clinical trial found an increased risk of death associated with the drug. Oncopeptides then stopped marketing the drug in the U.S.

FDA staff pointed to results in a confirmatory trial for Pepaxto, which did not meet the goal of progression-free survival, a measure of how long patients live without their cancer worsening. Staff also added that overall survival was worse in the Pepaxto group. Results showed a higher total number and percentage of deaths in the Pepaxto arm compared to the group given a standard multiple myeloma treatment. Regulators in Europe reached different conclusions about the drug, approving it last month. It is marketed there as Pepaxti. But the FDA advisory committee remained unconvinced by the company’s analyses and the European approval. On the question of whether the drug’s benefits outweigh its risks, the committee answered “no” by a 14 to 2 vote.

The standard qualifier for every FDA advisory committee meeting is that the regulator is not required to abide by the committee vote, but it usually does. If that holds true for Spectrum and Pepaxto, the chances don’t look good for a favorable decision from the FDA.

Here’s a look at other recent regulatory news.

—An experimental gut microbiome therapy from Ferring Pharmaceutical won the backing of an FDA advisory committee, which voted 13 to 4 that the treatment’s data are adequate to support its efficacy. Switzerland-based Ferring designed its therapy, RBX2660, to reduce the recurrence of C. difficile infection (CDI). The committee also voted 12 to 1 with one abstention on the question of whether the data are adequate to support the safety of the Ferring therapy in those 18 and older following antibiotic treatment for recurrent CDI.

—Children have been excluded from many clinical trials due to what the FDA now says was a “misperception that excluding them from research was in fact protecting them.” That thinking is changing and the FDA has issued draft guidance setting out an ethical framework for including and protecting children in clinical trials. The draft is open to public comment for the next three months before the FDA finalizes the guidance.

—The FDA placed a partial clinical hold on a pivotal study testing Viaskin, a peanut allergy patch in development by DBV Technologies. That study has not yet started but France-based DBV said the agency has asked for adjustments to the statistical analysis of the patch’s adhesion, among other changes. According to DBV, the FDA said these modifications are needed for the study to support a future biologics license application.

—Eli Lilly cancer drug Retevmo received FDA approval for treating advanced solid tumors characterized by a RET gene fusion. The accelerated approval covers the treatment of cancers that have progressed following at least one prior treatment. Retevmo won its initial accelerated approval in 2020 for the treatment of three RET-driven cancers: non-small cell lung cancer (NSCLC), thyroid cancer, and medullary thyroid cancer. With the latest tumor agnostic approval, the 2020 accelerated approval in NSCLC has been converted to a traditional one.

Clinical trials of a Merck HIV drug that were paused by the FDA last year can now resume, but at a lower dose. Merck also said it will no longer pursue development of the HIV drug, islatravir, for HIV prevention. The FDA placed multiple tests of the drug on full or partial holds after the observation that some patients treated with islatravir developed lower levels of two types of immune cells.

—Larimar Therapeutics was also able to resolve a clinical hold. Last year, the regulator paused a dose-ranging clinical trial evaluating the biotech’s treatment for Friedreich’s ataxia, a rare neuromuscular disorder, after deaths were reported in a monkey study. Those deaths all happened in monkeys given the highest dose of the drug.

The lift of the full clinical hold comes with the imposition of a partial hold. The planned Phase 2 trial now has a requirement that the FDA review data from a lower 25 mg dose group before the study escalates to a higher dose in the second cohort. Larimar said it expects to begin this study in the fourth quarter of this year; data are expected in the second half of 2023.

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When Biogen’s experimental treatment for amyotrophic lateral sclerosis (ALS) missed the main goal of a pivotal study last year, the drugmaker said further analysis could yield better results. Additional data now show that treatment over a longer period of time led to improvement on several measures of the neuromuscular disorder.

The latest clinical trial results were published Wednesday in the New England Journal of Medicine. The data lend additional support for the drug, tofersen, which has been submitted for FDA review and is expected to receive a regulatory decision in early 2023.

Tofersen is an antisense oligonucleotide, a type of drug comprised of small pieces of DNA or RNA. The Biogen drug addresses a subset of ALS patients whose disease is driven by mutations to the SOD1 gene. These mutations lead to abnormal versions of the SOD1 protein believed to contribute to motor neuron dysfunction and cell death. Tofersen is designed to bind to and degrade SOD1 messenger RNA, which in turn reduces synthesis of SOD1 protein.

The main goal of the randomized, placebo-controlled Phase 3 test of the drug was to evaluate ALS patients on various functional measures at 28 weeks. According to results reported last October, the observed patient improvement was not enough to show statistical significance. However, investigators at the time noted that the results showed reductions in SOD1 protein and neurofilaments, filaments found in neurons that are considered a potential biological indicator of neurodegenerative disease.

Biogen did not give up on the drug. In June, the company presented data analysis  in which the randomized study at 28 weeks was combined with an open-label extension study at 52 weeks. In that new 52-week analysis, Biogen reported slower declines in measures such as respiratory function and muscle strength in those who started on tofersen earlier—the patients who received the study drug at the start of the study compared with those who started on placebo and were switched over to tofersen at week 28 to begin the extension study. These are the results that are now published in the New England Journal of Medicine.

Timothy Miller, co-director at the ALC Center at the Washington University School of Medicine and the principal investigator of the tofersen clinical trial, said in a prepared statement that in addition to the lowering of SOD1 protein, the drug led to “substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process.” Miller added that looking at the results in the later time points in the open-label extension study show “meaningful clinical benefit.” The New England Journal of Medicine article notes that comparisons of earlier initiation of tofersen versus delayed initiation are still being evaluated in the extension stage of the clinical trial.

The 52-week data were part of Biogen’s submission seeking FDA approval. The FDA accepted that application in July, setting a Jan. 25, 2023 target date for a regulatory decision. At the time, the agency said it planned to convene an advisory committee meeting to discuss the application. The date for that meeting has not yet been set.

The published data for Biogen’s ALS drug come as an ALS drug from Amylyx Pharmaceuticals is making its way through regulatory review. Two weeks ago, an FDA advisory panel voted 7-2 in support of recommending approval of that company’s experimental ALS treatment, AMX0035. An FDA decision for the Amylyx drug is due by Sept. 29.

Meanwhile, another ALS drug developer, BrainStorm Cell Therapeutics, is taking a shot at FDA approval. Last year, the FDA called out Brainstorm’s analysis of its ALS drug, Nurown, saying that that in addition to missing the main clinical trial goal, the results fell did not show patient benefit. Nevertheless, Brainstorm said last month that it plans to seek FDA approval of its ALS therapy.

Photo: Adam Glanzman/Bloomberg, via Getty Images

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Red seal and imprint "FDA APPROVED" on white surface. FDA - Food and Drug Administration is a federal agency of the United States Department of Health and Human Services.

AstraZeneca and Daiichi Sankyo drug Enhertu is on a hot streak, winning an FDA approval in lung cancer that marks its second affirmative regulatory decision within the span of a week.

The FDA approval announced Friday covers the treatment of adults whose advanced cases of non-small cell lung cancer (NSCLC) express the cancer protein HER2. Those cancers must have received at least one prior systemic therapy. According to the FDA, Enhertu is now the first drug approved for treating NSCLC characterized by the HER2 mutation. Concurrent with Enhertu’s new approval, the agency also approved a Thermo Fisher Scientific companion diagnostic that detects this mutation.

Enhertu is an antibody drug conjugate, a type of therapy comprised of a targeting antibody linked to a toxic drug payload. The antibody component of Enhertu is designed to target HER2, a protein expressed on the surface of some cancer cells. The drug won its first FDA approval in 2019 for the treatment of HER2-positive breast cancers that have spread. On Aug. 6, the FDA expanded the drug’s approval to include the treatment of breast cancers characterized by levels of HER2 previously thought to be too low for a targeted therapy. That decision defined a new category of breast cancer patients, bringing them their first targeted therapy.

The latest Enhertu approval means the drug may now be used to treat the most common type of lung cancer. NSCLC accounts for about 80% of lung cancer cases, according to the American Lung Association. This approval was based on an interim analysis of data from Phase 2 data that enrolled 152 participants with HER2-positive NSCLC. The main study goal is to measure objective response rate to the drug, defined as the proportion of patients showing either a complete response or a partial response to the infused therapy. The objective response rate was 58% and the median duration of that response was 8.7 months. Response rates were consistent across the two doses that were tested. Higher rates of lung complications were observed at the higher dose; the approval covers the low dose. AstraZeneca said that results from the NSCLC clinical trial will be presented at a future medical meeting.

The most common adverse reactions reported in the clinical trial include nausea, a low white blood cell count, anemia, and low levels of immune cells called neutrophils—all of them consistent with previous tests of the drug. The most serious complication observed in the study was interstitial lung disease, which is characterized by scarring and inflammation. The drug’s label includes a boxed warning flagging this side effect.

“HER2-mutant non-small cell lung cancer is an aggressive form of disease which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit, said in a prepared statement. “Today’s news provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease.”

The regulatory decision for Enhertu in NSCLC is an accelerated approval that’s based on less evidence than is required of a standard approval. AstraZeneca and Daiichi Sankyo will need to conduct additional clinical testing to confirm the drug’s benefit to patients. The drug’s first approval in HER2-positive breast cancer was an accelerated one. That status was converted to full approval in May when the drug moved up in the sequence of cancer treatment options with the FDA O.K. of the drug as a second-line therapy. Enhertu is also approved for treating advanced HER2-positive gastric cancers.

Here’s a recap of some additional regulatory news from the past week:

—Tabrecta, a Novartis drug that won accelerated approval in 2020 for the treatment of advanced NSCLC, now has full FDA approval. The targeted therapy is a small molecule designed to target a particular genetic signature known as mesenchymal-epithelial transition (MET) exon 14 skipping. Conversion of the drug’s status to full approval is based on additional clinical testing that showed response rates consistent with earlier data.

—The European Medicines Agency told ProQR Therapeutics that the company needs to run another clinical trial for its RNA therapy for a rare eye disorder. The therapy failed a pivotal study earlier this year but ProQR had hoped that an additional analysis of the clinical data would be enough to support a regulatory submission. Rather than conduct another study, the Netherlands-based biotech said it will look to partner all of its ophthalmology assets and turn its focus to developing liver and central nervous system disorder drugs based on its RNA platform technology.

—The FDA rejected an Acadia Therapeutics application seeking to expand the approval of its anti-psychotic, Nuplazid, to include Alzheimer’s psychosis. According to Acadia, the FDA said that the data submitted were not from an adequate and well-controlled study and the company must run another clinical trial. The drug was first approved in 2016 as a treatment for the hallucinations and delusions experienced by patients who have Parkinson’s disease.

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Ahead of a planned booster vaccination campaign this fall, the U.S. government has locked up supply of Moderna Covid-19 vaccines designed to protect against both the original strain of the virus as well as the omicron subvariants that are now circulating widely.

According to terms announced Friday, Moderna will supply the government with 66 million doses of its booster vaccine candidate. The contract includes the option to purchase up to 234 million booster doses. Moderna could be paid up to $1.74 billion, depending on how many doses are ordered.

The Moderna vaccine, named Spikevax, received FDA approval in January for those 18 and older. That vaccine was designed to address the original strain of the novel coronavirus. The company has also been developing two different booster candidates, each a bivalent vaccine that protects against two different strains. Both of these new vaccines will protect against the original strain. One of them, mRNA-1273.222, will also contain the BA.4/5 omicron strain that is dominant in the U.S., consistent with booster guidelines that the FDA set last month. The second booster candidate, mRNA-1273.214, addresses the BA.1 subvariant, which may be more applicable to other regions in the world.

The contracted supply of Moderna boosters is in addition to the agreement the government struck for 105 million bivalent booster doses of the Pfizer/BioNTech Covid-19 vaccine, plus the option to purchase up to 195 million additional doses. Both boosters will need FDA authorization and a recommendation from the Centers for Disease Control and Prevention. If these new shots pass muster with both agencies, they could be ready to go into arms in early fall, the Department of Health and Human Services said. Citing unnamed sources, The New York Times reported that the Biden administration plans to offer the updated Covid-19 shots in September.

As of now, boosters have FDA authorization for those 50 and older as well as those 12 and older who have conditions that impair their immune systems. The Times reported that due to the rising number of Covid-19 cases, some federal health officials advocated for broadening booster eligibility of the current vaccine ahead of the rollout of the retooled versions. But after the companies assured government officials that they could deliver their bivalent boosters by mid-September, the FDA and CDC decided it would be better to focus on the fall vaccination campaign with the new versions of the shots, the Times reported.

According to the CDC, 603.7 million vaccine doses have been administered in the U.S. The agency calculates that 78.8% of the U.S. population has received at least one dose and 67.2% of the population is fully vaccinated (defined as those who have received the second dose of a two-shot vaccine or one dose of the single-shot Johnson & Johnson vaccine). Of those who are fully vaccinated, the CDC reports that 107.9 million people have received a booster shot. More than half of the total booster-eligible population has yet to receive a booster shot, the CDC’s latest data show.

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The FDA’s recent complete response letter (CRL) for vadadustat — an oral therapy evaluated for the treatment of anemia in patients with chronic kidney disease (CKD) — was a big surprise and disappointment for our community. The trials had quite convincingly demonstrated efficacy as measured by raising hemoglobin levels and safety as measured by major adverse cardiovascular events (MACE) for the dialysis-dependent population—findings that should have sealed the approval, but did not.

It was perplexing that the FDA decided against seeking insight from the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) for vadadustat, which is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Did the FDA’s experience with the roxadustat advisory committee meeting, in which they overwhelmingly voted against approving the drug for the treatment of anemia associated with CKD in the dialysis-dependent and non-dialysis-dependent patient populations, sound the death knell for vadadustat and the entire HIF-PHI class of drugs?

Roxadustat has already been approved in Japan, South Korea, Chile, and the EU. Vadadustat is approved in Japan and is currently pending approval in the EU. The FDA seems to be an outlier as a regulatory agency by failing to see the positive benefit/risk assessment of this drug class. Any potential safety concerns with HIF-PHIs that the FDA may have can easily be resolved with a long-term pharmacovigilance plan.

The FDA was primarily concerned with venous thromboembolism and vascular access thrombosis events with roxadustat; yet there was no indication that vadadustat had that safety issue. Data presented at the American Society of Nephrology’s annual meeting in 2021 specifically addressed thromboembolic complications and vascular access thrombosis in dialysis and non-dialysis patients and clearly showed that vadadustat was non-inferior to the study comparator, darbepoetin. This should have allayed the concerns that the CRDAC had with roxadustat, while distinguishing that vadadustat had a better safety record both in terms of MACE and of venous thromboembolism and vascular access thrombosis.

The fact that the FDA did not even request a CRDAC for vadadustat suggests that the regulators may have already made up their minds about this entire class of drugs. This is disappointing and unfortunate for America’s vulnerable kidney patients.

One of the greatest unmet needs in treating anemia is in the non-dialysis patient population, which lacks convenient treatment options. Erythropoietin stimulating agents (ESAs) are difficult to administer. These parenteral drugs may require patients to visit a healthcare facility for administration, which can be burdensome for patients and their caregivers, especially considering the frequency of administration. In contrast, HIF-PHIs are oral agents that improve both iron absorption and mobilization, thereby reducing the need for iron administration in anemic CKD patients. Considering all these factors, HIF-PHIs could be effective and more convenient for non-dialysis CKD patients who are receiving inadequate treatment today.

Medicare data indicate disconcerting findings: those 65 and older are more likely to have received a transfusion to treat their anemia than iron or ESAs during the two years prior to dialysis initiation. Transfusions are undesirable because they lead to allosensitization, potentially reducing the patient’s donor pool for a future transplant. This is counterproductive to the mission of the federal government’s Advancing American Kidney Health (AAKH) initiative, which aims to improve kidney transplantation rates. Moving forward, it will be critical for stakeholders to evaluate ways to align these incentives and the ability to administer an oral agent at home to treat anemia, avoid transfusions, and help fulfill the goals of improved transplantation rates. However, if the FDA has already made up its mind about the safety of this class of drugs, sadly, we will not see any significant improvements in the treatment of anemia for the non-dialysis patient population.

Dialysis-dependent patients are different from the non-dialysis patient population: 80% of individuals in the former group achieve their target hemoglobin levels with moderate doses of ESAs. However, the remaining 10-20% are hyporesponders for a variety of reasons usually related to inflammation.  With a novel mechanism of action, HIF-PHIs would likely be more effective in reducing hepcidin levels, thereby mobilizing iron, helping patients avoid transfusions, and improving quality of life related to higher hemoglobin levels. Another important point is that one of the AAKH initiative’s goals is to increase home dialysis rates to 40-50% of patients. Considering the burden associated with administering parenteral ESAs, HIF-PHIs would add value to the treatment plan of patients who do not require regular visits to a dialysis facility.

Impact of the FDA’s decision on the HIF-PHI drug class

Reflecting on how the FDA’s decision would impact other agents in the class that are currently under development, one has to wonder about daprodustat, another HIF-PHI currently under review by the FDA. Results published in the New England Journal of Medicine (NEJM), which were presented in November 2021 at the American Society of Nephrology annual meeting, showed non-inferiority for MACE in both dialysis and non-dialysis populations based on an intention to treat analysis—the gold standard for analyzing drug safety. MACE non-inferiority of daprodustat was demonstrated among the dialysis population in both intention-to-treat and the on-treatment analysis.

With the CRL for vadadustat, the FDA has made the puzzling decision to extrapolate the safety findings of vadadustat in the non-dialysis population to the dialysis-dependent population, despite non-inferiority data for the latter. According to Akebia, the developer of vadadustat, the FDA has cited hepatocellular injury and thromboembolic events, specifically vascular access thrombosis, as the basis for its rejection. However, the results published in NEJM clearly show these adverse events were no different than the active comparator—hepatocellular injury wasn’t an issue in either population. Table S7 of the supplemental information, which lists the emergent adverse events in the safety population, does show an increase in transaminases in the ESA-untreated non-dialysis patients treated with vadadustat (1.8% of patients) compared to darbepoetin (1.0% of patients). The difference, however, is negligible in the ESA-treated non-dialysis subgroups who received either vadadustat (1.2%) or darbepoetin (1.3%).

In my opinion, this is not a valid reason for rejecting the drug in the non-dialysis population that was studied, and most certainly not in the dialysis population.

The non-dialysis population treated with daprodustat demonstrated an increased incidence of esophageal and gastric erosions, as well as increased cancer risk compared to those treated with darbepoetin. While this was not observed in the dialysis patients treated with daprodustat, if the FDA takes a similar stand to vadadustat and extrapolates the safety results to both groups, it could jeopardize the approval of daprodustat in both populations.

I strongly urge the FDA to conduct a CRDAC for daprodustat so that we do not see a repeat of the non-transparent decision on vadadustat, where it appears to many that the FDA had unilaterally decided on the HIF-PHI class of drugs based on the findings with roxadustat. The FDA has apparently conflated concerns with one drug to concerns about the entire class. We would like to hear directly from experts on a CRDAC as they query the sponsor about a specific drug prior to an approval decision being made.  The FDA should consider each drug on its own merit instead of looking at these drugs as an entire class—both from an efficacy and safety perspective.

Another potentially valuable drug in the nephrology space, tenapanor, was rejected last year by the FDA citing less than robust efficacy, but there were no safety concerns.  However, the benefits of this drug still exist given that it could reduce the number of pills a patient needs to take to decrease serum phosphorus levels. Such treatment options are important in the patient-centered culture we are trying to achieve.  Nephrology has one of the lowest rates of new drug applications, despite the fact that nearly 40 million Americans are living with some form of kidney disease.

It is ironic that the AAKH and the Kidney Innovation Accelerator (KidneyX) -— both federal programs that were conceptualized to improve nephrology care, slow the rate of progression of CKD, and decrease the costs associated with treating end-stage renal disease care — are not able to realize their goals due to barriers to innovation in treatments for kidney disease resulting from the FDA’s track record of rejecting new drug applications for less-than-compelling reasons.

I have no doubt about the efficacy of the HIF-PHIs, and neither does the FDA, in my opinion. While the FDA reviewers are concerned with drug safety, they have left the door open for drug developers to conduct some additional safety studies, perhaps in smaller groups of patients who may be at higher risk for theoretical adverse outcomes. I am hopeful that the companies developing these drugs — often small startups — will find the resources or right partners to conduct these additional studies, although the challenges are great due to cost and the time involved in such trials.

Kidney disease patients need access to innovative therapies to expand treatment choices and improve quality of life. The FDA should closely examine whether it is applying the appropriate benefit/risk assessment for new drugs intended for this population. The FDA’s non-transparent rejection of vadadustat in the dialysis population, where efficacy is well established and there is no clear safety signal, represents a failure by the FDA to act in the best interests of the patients it was created to serve.

Editor’s Note: The author is on the advisory board of Akebia, which received the FDA rejection of vadadustat — an oral therapy evaluated for the treatment of anemia in patients with chronic kidney disease.

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Novartis is paying $100 million now for the opportunity to shorten the regulatory review of a rare disease drug candidates in the indeterminate future, a move that could save time and bring a potential blockbuster product to the market sooner, assuming it passes FDA muster.

The Swiss pharmaceutical giant has reached a deal to buy a priority review voucher from Mallinckrodt Pharmaceuticals. Such vouchers stem from an FDA program intended to incentivize the development of drugs for rare or neglected diseases. Voucher holders can shave the standard 10-month review time down to six months.

Companies can obtain a voucher by winning approval for a rare disease drug. In such cases, the voucher that’s awarded may be applied to a future product candidate. The other way to get a voucher is to buy one from a company that already has one. That’s what Novartis is doing. Dublin, Ireland-based Mallinckrodt earned its priority review voucher by landing FDA approval last year for StrataGraft, a regenerative medicine treatment for burn injuries. This product is made by growing human skin cells to form a scaffold upon which a burn patient’s own skin cells can grow.

Mallinckrodt has been reorganizing under bankruptcy protection. As an asset that can be monetized, the StrataGraft priority review voucher became part of the company’s reorganization plan. According to that plan, the trustee overseeing the company’s unsecured claims had the right to consult in Mallinckrodt’s marketing and sale of the voucher. The document also specifies that these creditors will receive 35% of proceeds from a sale of the voucher. That means that the $100 million transaction breaks down to $65 million for Mallinckrodt and $35 million for the creditors. According to a Mallinckrodt regulatory filing, that payment will be directed to a trust set up for general unsecured claims under the Chapter 11 plan. In mid-June, Mallinckrodt announced that it had emerged from bankruptcy.

Novartis has plenty of experience with priority review vouchers. The company applied a voucher to autoimmune drug Ilaris, seeking to expand the drug’s approval to gouty arthritis. The FDA rejected that drug application in 2011 and asked the company to provide more clinical data. Novartis was awarded priority review vouchers in 2017 with the approval for CAR T cancer therapy Kymriah and in 2019 for the approval of Egaten for the treatment of fascioliasis, a neglected tropical disease. The FDA’s 2019 approval of Zolgensma, the first gene therapy for spinal muscular atrophy, also came with a rare pediatric disease priority review voucher. Novartis successfully redeemed one of its vouchers with the 2019 approval of Beovu, an antibody drug that treats the wet form of age-related macular degeneration.

More recent transactions include Albireo Pharma’s sale of a voucher last year for $105 million, and BioMarin Pharmaceuticals’ February voucher sale that brought in $110 million. Albireo earned its voucher for Bylvay, a treatment for pruritus in patients with a rare liver disease; BioMarin for the approved dwarfism drug Voxzogo. In May, the voucher that BridgeBio Pharma earned from the  approval of metabolic disorder drug Nubrilvy sold for $110 million. In each instance, the voucher purchasers were not disclosed.

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A Bristol Myers Squib cancer drug made by engineering a patient’s own immune cells is now approved to treat patients in earlier stages of their disease, a regulatory decision that expands the number of patients that can be reached with this type of personalized cell therapy. The decision could also give BMS an edge over a rival cell therapy marketed by Gilead Sciences.

The CAR T-therapy from BMS, named Breyanzi, was initially approved last year as a treatment for diffuse large B-cell lymphoma, (DLBCL) a type of non-Hodgkin lymphoma in which the body produces abnormal B lymphocytes. Standard treatment is chemotherapy plus the antibody drug Rituximab. When that treatment doesn’t work or the cancer relapses, the next treatment option is an autologous stem cell transplant.

Breyanzi’s initial approval made it a third-line treatment for DLBCL patients whose cancer relapsed or has not responded to two earlier therapies. The expanded approval of the drug announced late Friday moves the drug up in the treatment hierarchy and makes it a second-line therapy for patients whose disease has relapsed within 12 months of the initial chemotherapy regimen. That matches the expanded approval earlier this year of Gilead Sciences’ cell therapy, Yescarta. Furthermore, Breyanzi’s additional approval also covers those who are not eligible for a stem cell transplant.

Leo Gordon, an investigator in Breyanzi’s PILOT study and a professor of medicine at Northwestern University, said factors that may make patients bad candidates for a stem cell transplant include age, poor kidney or heart function, or low scores according to an assessment of frailty. Usually, such patients would receive palliative care to ease the cancer’s symptoms.

“We thought there was a possible place for CAR T-therapy,” Gordon said during an interview earlier this month at the annual meeting of the American Society of Clinical Oncology. “The purpose of this is to get another option for patients for what is considered to be the standard [of care treatment]. That’s why this is an important group to look at.”

CAR T-therapy is a personalized treatment made by harvesting a patient’s T cells and engineering them to target a protein on the surface of cancer cells. Those immune cells are multiplied in a lab and then infused back into the patient. Expanded approval of Breyanzi was based on the results of two studies evaluating the drug as a second-line therapy.

The TRANSFORM study evaluated Breyanzi in 184 patients still eligible for a stem cell transplant. The main goal was to measure how long a patient remains free of certain cancer complications. At one year, 45% of patients treated with Breyanzi achieved this mark compared with 24% of those who received standard therapy. Event-free survival in the treatment group was an estimated 10.1 months compared with 2.3 months in the control arm. Of those patients who received standard treatment, nearly half went on to receive an autologous stem cell transplant.

Measuring complete response and overall response were the main goals of PILOT, an open-label study that enrolled patients with a median age of 73. Gordon said that efficacy in PILOT was similar to what was observed in healthier and younger patients who were evaluated in tests of the drug as a third-line therapy. The median duration of response has not yet been reached but in the 61 patients, 54% achieved a complete response. “That is actually better than what we would expect for a transplant,” Gordon said.

The major safety risks of CAR T-therapies as a class include an immune response called cytokine release syndrome and toxic effects in the brain. Gordon said the cytokine release syndrome cases observed in the latest Breyanzi study were mild to moderate. While some patients had severe neurotoxicity, Gordon said no one had to go to the intensive care unit and everyone recovered. About 20% of patients were treated on an outpatient basis.

In a research note sent to investors on Monday, William Blair analyst Matt Phipps noted that compared to Yescarta, Breyanzi’s broader label as a second-line treatment gives it access to a bigger pool of patients that Gilead’s drug is not approved to treat.

“We assume around 40% of patients are refractory or will relapse at some point following first-line therapy, and with 50% of these patients being transplant ineligible, around 6,000 patients per year could be eligible for Breyanzi based on PILOT,” Phipps wrote. “Thus, this approval clearly provides Bristol Myers with a bigger opportunity with less CAR T-competition.”

Breyanzi accounted for $87 million in total revenue in 2021, according to BMS’s financial reports. For the first quarter of this year, the drug tallied $44 million in sales. Phipps said that Breyanzi’s new approval and broad label are positive signs for BMS as the company looks to other drugs that can offset patent expirations facing key products in coming years. He added that BMS projects Breyanzi could top $3 billion in annual sales by the end of the decade.

Photo by Bristol Myers Squibb

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Breast cancer cells

Athenex’s lead drug candidate, an oral formulation of the chemotherapy paclitaxel, is intended to bring patients comparable, if not better, efficacy and fewer side effects than the intravenous version. But the company now faces questions about the drug’s safety in the wake of an FDA rejection.

Buffalo, New York-based Athenex announced the rejection of the cancer drug Monday. According to the company, the regulator recommended the biotech conduct a new clinical trial in metastatic breast cancer patients. The agency also suggested the company take steps to mitigate the drug’s toxicity.

Shares of Athenex fell sharply after the FDA rejection was announced, and closed Monday at $5.46 apiece, down nearly 55% from Friday’s closing stock price.

Paclitaxel, also known as Taxol, is a widely used chemotherapy for treating breast, ovarian, and lung cancers. Intravenous dosing of the drug can cause adverse reactions. To mitigate those effects, cancer patients are given steroids and antihistamines prior to dosing of the chemotherapy. Other side effects of intravenous paclitaxel include nerve damage, hair loss, and neutropenia, which is an abnormally low level of a type of white blood cell called neutrophils. Those side effects may reduce how much of a dose of the chemotherapy a patient can receive.

Athenex’s version of paclitaxel is given in combination with another drug, encequidar. According to the company, this compound blocks a protein in the intestinal wall that limits the absorption of chemotherapies. In results of a Phase 3 study testing Athenex’s oral paclitaxel in patients with metastatic breast cancer, the company reported its drug met the main goal of showing statistically significant improvement in the overall response rate compared against treatment with the IV version of the chemotherapy.

The company also reported that its drug can reach levels in the blood comparable to IV paclitaxel, and for a longer period of time. The company said in securities filings that this capability may translate to a better clinical response to the therapy. In the 402-patient Phase 3 study, Athenex observed a higher tumor response rate along with lower incidence and severity of nerve problems compared to IV paclitaxel.

Athenex said that the agency’s complete response letter cited the risk of an increase in problems related to neutropenia in the oral paclitaxel arm compared with the group treated with the IV formulation. The FDA also expressed concern about how the results of the study primary endpoint were evaluated under blinded independent central review, a group of independent physicians. According to Athenex, the FDA said there may have been “unmeasured bias and influence” on the review.

Speaking on a conference call, CEO Johnson Lau said the company was “surprised and extremely disappointed” by the FDA’s rejection. The neutropenia concerns cited are a known risk of paclitaxel, he said. Lau added that the review remained blinded, was conducted by independent radiologists, and the regulator had not issued any formal warnings flagging problems at the imaging lab.

The FDA’s recommendation that Athenex conduct another clinical trial specified that the study should include patients more representative of the U.S. population. Rudolf Kwan, the company’s chief medical officer, said on the call that none of the clinical trial sites were in the U.S. But he added that the company had discussed the clinical trial design with the regulator, and the single study, as proposed by the company, was understood to be sufficient to support approval if the results were positive.

Lau said that the company plans to request a meeting with the FDA to discuss the letter and clarify the scope of the new clinical trial needed to address the agency’s concerns.

“Whether it requires the whole study be done in U.S., we’ll have to clarify in the meeting,” Lau said.

Though Athenex has a pipeline of clinical-stage cancer therapies, company currently generates most of its revenue from the sales of generic injectable products. In 2020, it reported more than $105 million in product sales, a 73% increase over 2019 sales. In its financial report of fourth quarter 2020 and full-year results, Athenex attributed the revenue increase to growing sales of specialty pharmaceutical products used to treat hospitalized Covid-19 patients. As of Dec. 31, 2020, Athenex had $86.1 million in cash and $138.6 million in short-term investments.

Photo by American Cancer Society/Getty Images

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The FDA has authorized Johnson & Johnson’s Covid-19 vaccine for emergency use, adding a third vaccination option—one that comes with storage and distribution advantages.

The regulatory decision followed the review of an FDA advisory panel, which voted unanimously on Friday to recommend authorization of the vaccine. J&J said it has begun shipping its vaccines to the federal government, which will manage distribution. The company expects to deliver enough vials for the vaccination of more than 20 million people in the U.S. by the end of March, ramping up to 100 million vaccinations by mid-year.

The J&J shot joins the messenger RNA vaccines developed by Moderna and partners Pfizer and BioNTech as the only authorized Covid vaccines in the U.S. The mRNA vaccines must be transported and stored at ultra-cold temperatures well below temperatures of typical medical freezer equipment. However, vaccination sites now have a little more flexibility in how they can store mRNA vaccines. Last week, the FDA approved a request from Pfizer and BioNTech to permit storage of their vaccine at pharmaceutical-grade freezers for up to two weeks.

The J&J vaccine can be transported and stored at refrigerator temperatures, making it a better option for rural areas or vaccination sites that don’t have the specialized freezer equipment required to store the mRNA vaccines. It has the additional advantage of being a single shot, unlike the mRNA vaccines that are given as two doses weeks apart. A single shot avoids the challenges of getting people to return for a second injection.

“The potential to significantly reduce the burden of severe disease, by providing an effective and well-tolerated vaccine with just one immunization, is a critical component of the global public health response,” Paul Stoffels, J&J’s chief scientific officer, said in a prepared statement. “A one-shot vaccine is considered by the World Health Organization to be the best option in pandemic settings, enhancing access, distribution and compliance.

The J&J vaccine uses a virus to fight a virus. The company’s Janssen subsidiary takes adenovirus, which causes the common cold, and engineers it so that it cannot replicate and does not cause illness. This engineered virus becomes the vehicle that transports into cells a piece of DNA from SARS-CoV-2, the novel coronavirus. Cells use that genetic material to make the spike protein found on the surface of SARS-CoV-2. Those proteins spark the immune response that leads to immunity. This vaccine technology, which J&J calls AdVac, is the basis of the company’s Ebola vaccine, which was approved by the FDA in 2019.

The FDA authorization for J&J’s Covid vaccine was based on results from a global, placebo-controlled Phase 3 study that enrolled nearly 44,000 volunteers. Those participants were followed for a median of eight weeks. The main goal of the study was to evaluate the first occurrence of moderate-to-severe Covid infection with the onset of symptoms after 14 days, and then after the 28-day mark.

Overall, the J&J vaccine was about 67% effective in preventing moderate-to-severe or critical Covid infection after two weeks. After 28 days, the vaccine was about 66% effective at preventing infection. The FDA added that the J&J vaccine was about 77% effective in preventing severe or critical illness two weeks after vaccination. After 28 days, the vaccine was 85% effective in preventing severe or critical illness.

The most common side effects reported from the studies were pain at the injection site, headaches, fatigue, muscle aches, and nausea. The FDA said these side effects were mostly mild to moderate and lasted for a day or two. J&J does not yet have enough data to determine how long protection from the vaccine lasts. The studies conducted to date also do not show whether the vaccine stops people from transmitting the virus. As part of the emergency authorization, J&J must continue to collect data about its vaccine and report and serious adverse events.

The J&J vaccine is given as a 0.5 mL intramuscular injection. The vaccine is shipped in vials, each containing five doses. The company estimates the vaccine will remain stable for two years stored at minus 4 degrees Fahrenheit (minus 20 degrees Celsius). At refrigerator temperatures in the range of 36 to 46 degrees Fahrenheit (2 to 8 degrees Celsius), the company says the vaccine can be stored for up to three months. The company will deliver the vaccine with the same cold chain currently used to ship its other medicines.

The federal government will manage the allocation and distribution of the J&J vaccine according to guidelines set by the Center for Disease Control and Prevention’s Advisory Committee on Immunization Practices. Johnson & Johnson said that it plans file an application seeking a formal FDA approval later this year. The company is also seeking authorizations for its vaccine in other markets.

Photo: Esben_H, Getty Images

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The U.S. is one step closer to making available another Covid-19 vaccine after a panel of experts voted unanimously Friday to recommend emergency use authorization for a shot developed by Johnson & Johnson.

The independent panel, comprised of mostly physicians, voted 22-0 to support the vaccine with no one abstaining. These votes aren’t binding on the FDA, but the agency often follows the recommendations of its panels. A decision could come as early as this weekend. The two Covid vaccines currently cleared for emergency use received their authorizations the day after their respective advisory panel meetings.

The Johnson & Johnson vaccine would offer an alternative to the ones currently available from the Pfizer and BioNtech alliance, and Moderna. Those messenger RNA vaccines must be distributed and stored at ultra-cold temperatures, then thawed before use. Those shots are given as two doses, weeks apart. The J&J vaccine can be kept at refrigerator temperatures. Another key difference is that the J&J jab requires a single shot. Together, those features will make the J&J vaccine easier to distribute to more people in more places through distribution channels that are already in place.

Panel members expressed support for the J&J vaccine, saying that the safety and efficacy data supported its authorization. But panelists also cautioned the public against picking vaccine favorites.

“It’s important that people do not think one vaccine is better than another,” said Cody Meissner, an infectious disease expert and professor of pediatrics at the Tufts University School of Medicine. “There is no preference for one vaccine over another and all vaccines work with what appears to be equal safety and equal efficacy as of this time.”

Emergency authorization is not the same as an approval. Federal law permits the FDA to allow marketing of unapproved medical products for emergency situations, such as a pandemic. Authorizations only last for the duration of the emergency. These authorizations can also be revoked if new data show that the product is not safe or effective. Stanley Perlman, a professor in the departments of microbiology and immunology at the University of Iowa, said that while the clinical studies to date have produced data about the vaccine’s safety and efficacy, it would be “nice to have more.”

The J&J vaccine may be new, but compared to the mRNA vaccines, the technology behind it has bit of a longer track record. J&J vaccine makes it using its AdVac technology, the same platform that produced the company’s Ebola vaccine, which the FDA approved in 2019. The technology takes the virus that causes the common cold and modifies it so it doesn’t cause illness. That engineered virus is the delivery vehicle that ferries into cells a snippet of genetic code for the novel coronavirus’s spike protein. The genetic material serves as the blueprint from which the body’s cells produce spike proteins. The immune system responds by producing antibodies to those proteins, conferring immunity.

The clinical data to date for J&J Covid vaccine covers 44,000 adults from all over the world. In Phase 3 data reported in late January, the vaccine was 66% effective overall in preventing moderate-to-severe infection, 28 days after vaccination. Furthermore, the vaccine showed 85% efficacy in preventing severe disease, and showed complete protection against Covid-related hospitalization and death, also measured at day 28.

Those marks look inferior to the greater than 90% efficacy demonstrated in mRNA vaccine trials. But cross-trial comparisons are difficult and can be misleading because trials have different designs and different goals. Also, the mRNA studies were conducted earlier in the year when there were fewer variants circulating. Public health experts have said that if those vaccines were tested under current conditions, their efficacy rates might be lower, too.

Plans are already underway to gather more data about J&J’s shot, including a study of the vaccine in children and teens. Johan Van Hoof, the global head of the infectious diseases and vaccines for J&J’s Janssen subsidiary, told the advisory panel that a clinical trial testing the vaccine in those 17 and younger is expected to begin this spring. He also said that the company is assessing how the vaccine responds to variants of the novel coronavirus.

Shortly after Friday’s meeting, the FDA issued a statement saying that it would “rapidly work” with J&J toward finalization and issuance of an emergency use authorization. The agency added that it has notified federal partners involved in the allocation and distribution of vaccines, so that they are ready.

Photo: Getty Images, Sezeryadigar

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