Jaime Rosenberg

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Like so much else in healthcare and beyond, a large question hangs over drug development in 2021 and the pace of FDA approvals: How much of an effect will COVID-19 have?

Because the majority of FDA approvals in the latter part of 2020 were based on results of trials conducted before the pandemic, the full impact of the pandemic on approvals may not become evident till this year. When the pandemic reached the United States in March and lockdowns throughout the country began, some active trials paused, many trials set to start were delayed, and new COVID-19-focused trials commenced. In just March and April, 905 clinical trials were suspended as a result of the pandemic, according to a study published in the September 2020 issue of 

. Meanwhile, a slew of others were rapidly launched to assess potential COVID-19 vaccines and treatments.

Between 20% and 25% of trials suspended enrollment as a result of the pandemic, according to Kenneth Getz, MBA, the deputy director of the Tufts Center for the Study of Drug Development in Boston. But Getz says that following delays of four to six months, most of those trials have now resumed as trial investigators adapted to using more remote or virtual methods. Approximately one-third of ongoing clinical trials started moving to a remote model very soon after the pandemic hit, but almost half (45%) continued following the original protocol approach, with patients coming into trial centers for visits, says Getz. Most of the trials that stuck with in-person visits were testing drugs for serious diseases such as cancer.

Getz says institutional review boards, ethical review committees and regulatory agencies deserve credit for helping with recruitment by allowing for some adjustments to trial design. Although some delays in getting the studies underway were inevitable, anecdotal reports suggest that once people were enrolled in a trial, they stayed enrolled, says Getz.

It remains to be seen how new, more virtual trial models will affect collection and reporting, says Getz. While conducting trials with more remote checks and monitoring makes participation more convenient for study volunteers and may reduce the number of dropouts, recruitment amid the pandemic is likely to be a struggle. 

“A lot more people are more aware of clinical trials, but they think that participation may be riskier or less safe, especially if there might be some exposure to the coronavirus if they’re involved in a hybrid study that involves some in-person visits as well as some at-home visits,” says Getz.

Another worry of drug developers is whether the FDA is so focused on COVID-19 vaccines and treatments that review of other drugs will languish, notwithstanding Prescription Drug User Fee Act timelines. Drug developers and others are concerned that the agency is spread too thin and, as a result, fewer drugs will be reviewed and approved.

Aside from additional COVID-19 vaccines, perhaps the most anticipated (and possibly most controversial) approval decision this year concerns aducanumab, a monoclonal antibody developed by Biogen and Eisai Co. Ltd., a Japanese company, as a treatment for Alzheimer’s disease. Current treatments for Alzheimer’s are only modestly effective, and recent attempts to find better ones have foundered in late-stage trials. With baby boomers entering old age, the market for an effective drug for Alzheimer’s disease would be enormous.

Aducanumab looked like it was going to join the long list of failures when Biogen and Eisai said in early 2019 early that they were shelving the drug after negative results from in two trials. Later that year, though, they reversed course and said further analysis suggested efficacy.

The agency seems to agree with the companies, judging by a document that became public late last year. But a watchdog group, Public Citizen, accused the agency of “inappropriately close collaboration” with the drug’s developers. Days after the positive FDA assessment, the up-and-down prospects of aducanumab took a downturn when an advisory committee of outside experts voted overwhelmingly against approval. Aimee Tharaldson, Pharm.D., senior clinical pharmacist of Emerging Therapeutics at Express Scripts, says she believes that approval is unlikely. A final decision is expected by March, but the schedule may hinge on the timing of President-elect Joe Biden’s selection of an FDA commissioner and the Senate confirmation needed for that person to assume the top post at the agency.

Another therapeutic area to keep an eye out for in the coming year is atopic dermatitis, the most common type of eczema. There are drugs in late-stage clinical development for moderate-to-severe atopic dermatitis.

Several of these drugs are Janus kinase (JAK) inhibitors, a type of disease-modifying antirheumatic drug. Pfizer’s abrocitinib seems headed for approval by April. AbbVie’s JAK inhibitor, Rinvoq (upadacitinib), which is currently approved as a treatment for rheumatoid arthritis, is expected to get an added indication for atopic dermatitis by June. Eli Lilly and Company’s Olumiant (baricitinib) may also be approved for atopic dermatitis this year. In November 2020, the FDA issued an emergency use authorization for a combination of Olumiant and remdesivir as a treatment for COVID-19. In addition, Leo Pharma’s tralokinumab, a novel treatment given as subcutaneous injection every two weeks, is expected to be approved this year as a treatment for atopic dermatitis.

Chimeric antigen receptor (CAR)T-cell therapy involves taking a patient’s T cells, altering them in a laboratory so they attack cancer cells and then reinfusing them. Currently approved as a treatment for acute lymphoblastic leukemia and several different types of lymphoma, CAR-T treatment is edging its way into the mainstream and may be approved for multiple myeloma this year. Researchers presented positive results for two CAR-T trials for the blood cancer last month at the annual meeting of the American Society of Hematology (ASH). Janssen’s ciltacabtagene autoleucel, which is expected to be approved in the second half of the year, showed a near perfect (97%) overall response rate over 12.4 months in patients whose disease had worsened after multiple treatments. At a median follow-up of 12.4 months, the median length of response and progression-free survival endpoints were not reached.

Bristol Myers Squibb and Bluebird bio’s CAR-T therapy, idecabtagene vicleucel, is expected to be approved in March as a treatment for multiple myeloma. Results of a phase 1 trial, which came out ahead of the ASH meeting but were also presented there, showed a response rate of 76% and a complete response rate (no detectable cancer after treatment) of 39%. The median length of response was 10.3 months.

Also in the offing this year are possible approvals for treatments for two rare diseases.

Orphazyme’s arimoclomol is an HSF1 stimulant pending approval for the treatment of Niemann-Pick disease type C, a rare, progressive lysosomal storage disorder that affects approximately 200 people in the U.S. With no approved treatments for the disease, most patients die by age 40. An FDA decision on the treatment is expected March 21.

PTC Therapeutics’ eladocagene exuparvovec is a gene therapy for the treatment of aromatic L-amino acid decarboxylase deficiency, which has been identified in approximately 100 patients in the U.S. The one-time infusion is expected to be priced somewhere between
$2 and $3 million.

Jaime Rosenberg is a freelance writer based in Jersey City, New Jersey.

Articles

The industry is adjusting to the pandemic, but FDA approvals could dip this year. Several new drugs for atopic dermatitis may get the agency’s green light.

What’s on the horizon for drug development in 2021?

2021 stands to be pivotal year for HIV/AIDS prevention and treatment. Many researchers and advocacy groups are heartened by President-elect Joe Biden’s selection of 

, M.D., M.P.H., to be the CDC director of the new administration. Walensky, chief of infectious diseases at Massachusetts General Hospital and a professor at Harvard Medical School, is a well-known HIV/AIDS researcher. The CDC director does not require Senate confirmation so there’s no reason to believe that Walensky won’t heading up the federal government’s prime infectious disease agency.

Walensky will be taking the reins at the CDC at a crucial time in the course of the HIV/AIDS epidemic. Many people infected with HIV don’t have a diagnosis, so diagnosed cases don't tell the full story by any means, Even so, it's notable that the number of diagnosed cases has been declining. In 2018, the latest year for which a tally is available, 37,968 new cases were diagnosed, which is 2,868 fewer cases than the 40,836 diagnosed in 2014. In 2018, 5,425 Americans died from the AIDS.

Two years ago, the Trump administration promulgated a 10-year plan to end 

. The plan largely hinges on the availability and uptake of medications to both prevent and treat HIV, so medical innovation and ways to disseminate such innovation are crucial.

Here are five developments to look out for in 2021 that may have a major effect on HIV/AIDS treatment and prevention:

1a. Awaiting a decision from the FDA on long-acting injectable Cabenuva

So far, treatment for HIV involves taking pills that need to be taken daily. That may change this year with the advent of treatments that can be injected and don’t need to be taken daily. The implications of long-acting injectable treatment are great, as they will likely improve adherence to treatment and eliminate the daily reminder of treatment.

The FDA is expected to issue its decision on ViiV Healthcare’s  injectable Cabenuva—a combination of cabotegravir and rilpivirine—sometime in the next few months. ViiV Healthcare, a joint venture by GlaxoSmithKline and Pfizer, is seeking approval for the treatment regimen in adult patients with HIV whose viral load is suppressed and who are not resistant to cabotegravir or rilpivirine.

In phase 2 and 3 clinical trials, the treatment combination, given as two injections — one of cabotegravir and the other, rilpivirine — once a month by a healthcare provider, was shown to be equally as effective as traditional oral options. While it did cause injection-site reactions, 

 Cabenuva over the alternative daily oral option.

1b. Inching closer to a twice-yearly injectable for treatment-resistant patients

Gilead is expected to complete regulatory filings this year for their long-acting self-injectable HIV treatment lenacapavir. Gilead’s long-acting injectable only has to be injected once every six months, a far cry from the daily oral treatments.

If approved, the HIV-1 capsid inhibitor will be the first approved treatment of its kind and is meant for heavily treated patients who have become resistant to multiple drugs—a particularly difficult-to-treat group of patients—in combination with other treatments.

The anticipated regulatory filings will come on the heels of 

 from the phase 2/3 CAPELLA trial of 36 patients. The data showed that patients receiving lenacapavir were significantly more likely to meet the study’s primary endpoint of a 0.5 log10 or greater reduction in viral load—a marker chosen to measure a relevant change in the amount of virus a patient has—compared with placebo.

Excitement is also mounting for the very real possibility that a long-acting injectable to prevent HIV will soon be approved. As 2020 came to a close, the FDA granted breakthrough designation to ViiV Healthcare’s cabotegravir—one of the two drugs in HIV treatment candidate Cabenuva—for the prevention of HIV. Cabotegravir is administered once every 2 months.

 to effectively prevent HIV infection in men who have sex with men and transgender women in a phase 2b/3 trial comparing the vaccine with Truvada, an FDA-approved HIV prevention oral option taken daily. The study, HPTN 083, was actually halted early because an interim analysis indicated that it was effective. The data showed that cabotegravir injection was 66% more effective at preventing HIV infection than Truvada.

3. Continuing the quest for an HIV vaccine

Despite all the progress in HIV treatment, development of an effective HIV vaccine has proved to be elusive. But vaccine research continues. Janssen’s late-stage

 vaccine candidate, which is expected to see initial results from the phase 2b Imbokodo study as early as this year. As of July last year, all 2,600 patients in the study 

4. Gaining more coverage for HIV prevention medication

As the HIV community awaits for the approval of long-acting injectable cabotegravir, a new rule will make current HIV prevention treatments more accessible. Private insurers are now gearing up to offer full coverage for these treatments, also known as PrEP, including Gilead’s Truvada and Descovy, as well as Teva’s newly available generic version of Truvada, for patients at high risk of acquiring HIV.

Coverage of PrEP, which reduces the risk of acquiring by HIV by more than 90%, will likely have significant implications for many patients at risk of HIV, as out-of-pocket costs for the treatments can run patients $1,000 each year 

 because insurance does not always cover the full price of the treatment.

The move follows the U.S. Preventive Services Task Force—an independent panel that reviews the effectiveness of and provides recommendations for preventive services—giving PrEP for HIV prevention an “A” recommendation back in 2019. Under the ACA, most insurers must cover preventive services that receive an “A” or “B” rating from the group.

Injectable treatments may start to replace daily pills.

5 developments to watch for in HIV/AIDS treatment and prevention in 2021

Some notable 2020 FDA approvals of new drugs

 (teprotumumab-trbw). Approved in January, Tepezza is the first and only FDA-approved treatment for thyroid eye disease, a rare and progressive inflammatory disease that affects the eye and nearby orbital tissues that can result in eye protrusion and visual impairment.

 (ozanimod). Approved in March, Zeposia is a treatment for adults with relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS, clinically isolated syndrome and active secondary progressive MS. Although it competes with Gilenya (fingolimod) and Mayzent (siponimod), the sphingosine-1-phosphate receptor modulator does not require first-dose monitoring for bradycardia (a slow heart rate).

 (risdiplam). Approved in August, Evrysdi is the first oral drug approved to treat spinal muscular atrophy (SMA). The two other drugs approved for some patients with SMA are Spinraza (nusinersen), administered as an intrathecal injection once every four months, and Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy administered as a one-time IV injection.

Some notable 2020 FDA approvals of new oncology drugs

 (sacituzumab govitecan-hziy). Approved in April, Trodelvy is an antibody-drug conjugate for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior therapies. The antibody “finds” the cancer, and the drug attacks the cancer.

 (lurbinectedin). Approved in June, Zepzelca is an alkylating drug for adult patients with metastatic small cell lung cancer who have progressed on or after chemotherapy.

(isatuximab-irfc). Approved in March, Sarclisa is a monoclonal antibody that binds to the CD38 receptor on multiple myeloma cells. The FDA approval is for Sarclisa in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies.

 (capmatinib). Approved in May, Tabrecta is a kinase inhibitor used to treat metastatic non-small cell lung cancer. It is one of an increasing number of agents that home in on cancer cells with a particular mutation, in this case a mutation that leads to MET exon 14 skipping.

Every nook and cranny of American healthcare has been affected by the COVID-19 pandemic, and drug development and approvals are no exception. But, remarkably, the number of drug approvals coming from the FDA showed no signs of slowing down this year, with 47 novel drugs approved as of the beginning of December, among them a record number of oncology drugs. Judging by Prescription Drug User Fee Act dates — dates by which the FDA is supposed to complete its review of an application — it looks like the number of FDA-approved new drugs this year will easily surpass the 48 approved last year but will probably fall short of the record of 59 approvals two years ago.

Does that mean that drug development escaped unscathed? No. As FDA drug approvals rolled in during the first half of the year, drug developers and those dependent on the pharmaceutical industry fretted that the number of approvals would fall off sharply as the year went on and the pandemic continued. In March, when the pandemic hit the United States, several drug companies moved to halt or delay new studies and patient enrollment.

But there was still some pre-pandemic momentum to the drug pipeline. If the pandemic has slowed down drug development and approvals, it will likely become more evident next year and the year after. Investigators are still trying to figure out safe, reliable ways to enroll and monitor patients in clinical trials, although steps have already been taken to do some trials remotely.

Looking at it from another perspective, the pandemic hasn’t crimped the drug pipeline so much as tested how fast it can expand and adjust as companies — with government assistance — raced to develop treatments and vaccines for a disease that didn’t exist before this year.

It hasn’t been all smooth sailing. According to many experts, the FDA emergency use authorizations (EUAs) for hydroxychloroquine, the drug touted by President Donald Trump, and convalescent plasma were a mistake — and in June the FDA did wind up revoking the EUA for chloroquine and hydroxychloroquine. The wisdom of full-fledged approval for Gilead’s Veklury (remdesivir) has also been questioned. On the other hand, as we went to press, the FDA was considering emergency use authorizations for two COVID-19 vaccines, one developed by Pfizer and BioNTech, a German company, and the other by Moderna, a biotech company in Cambridge, Massachusetts.

Meanwhile, in the “normal,” non-COVID-19 pipeline, there has been a marked shift recently in the types of drugs the FDA approves. The agency is approving more specialty drugs — expensive drugs for relatively rare diseases — than so-called traditional drugs. In fact, over the past five years, two-thirds of FDA approvals have been for specialty drugs, and 2020 is no exception, says Aimee Tharaldson, Pharm.D., senior clinical pharmacist of Emerging Therapeutics at Express Scripts. So far, 68% of 2020 approvals have been for specialty drugs.A large proportion of new drug approvals this year have been for oncology drugs. So far, 18 novel oncology drugs have gotten the nod from the FDA, and a few more may be approved before the year is over. According to Tharaldson, the oncology approvals this year break the record number of 17 approved in 2018.

The FDA is also approving orphan drugs at steady clip; Tharaldson notes that more than half of the new drugs approved so far in 2020 are in that category. Orphan drugs are a subset of specialty drugs that the FDA puts on a separate approval track that makes the developers eligible for a variety of incentives.

Two of the notable orphan drug approvals are for neuromyelitis optica spectrum disorder, a rare autoimmune disease that affects approximately 10,000 people in the United States. The disease, which can be misdiagnosed as multiple sclerosis, is characterized by inflammation of the optic nerve and spinal cord. Severe cases, can lead to blindness and impaired mobility. In June, the FDA approved Uplizna (inebilizumab-cdon), a CD19-directed antibody and, in August, Enspryng (satralizumab-mwge), an interleukin 6 inhibitor.

It is a different story with generics. According to 

, the online publication of the Regulatory Affairs Professionals Society, 2020 did not bode well for future generic competition. In fiscal year 2020, the FDA approved 909 abbreviated new drug applications (ANDAs) for generics, a 22% drop from fiscal year 2019, when the FDA approved 1,171 ANDAs.

Jaime Rosenberg is a freelance writer based in Jersey City,

Pre-pandemic momentum helped keep the number of novel therapies approved by the FDA high, and then COVID-19 tested just how fast the pipeline could adjust and expand.

Jaime Rosenberg

Articles

What’s on the horizon for drug development in 2021?

5 developments to watch for in HIV/AIDS treatment and prevention in 2021

2020 drug approvals: not bad, considering