Jaime Rosenberg

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Highly anticipated data on Gilead’s novel twice yearly HIV treatment have been announced, suggesting that the therapy is effective in heavily pretreated patients who have stopped responding to other treatments. Early data from a second trial is also indicating that the treatment may yield benefits for patients who have not yet received treatment for HIV.

Presented at the International AIDS Society Conference in July, the results for lenacapavir have implications for the multidrug-resistant patients. The 

 from the Phase 2/3 CAPELLA study showed that lenacapavir was able to suppress HIV in those patients with 81% of the 36 patients having an undetectable level of HIV six months after receiving the treatment.

“Despite the advances in treating HIV infection, there remains an unmet need for treatment options for people who struggle with multi-drug resistance,” said Jean-Michel Molina, M.D., professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, in a prepared statement. “The CAPELLA results are exciting as they demonstrate that an undetectable viral load is achievable in a patient population that has typically had challenges with viral suppression over the course of their journey living with HIV.”

Lenacapavir is currently being evaluated by the FDA for approval in these patients, with the CAPELLA trial forming the basis of Gilead’s application. If approved, it will become the first approved HIV treatment that can be administered just twice a year. Once-daily pills have been the main form of HIV treatment. So far, just one extended-release, injectable treatment for HIV has been approved, ViiV Healthcare’s Cabenuva, a combination of cabotegravir and rilpivirine, which is injected once a month.

These newly released findings for lenacapavir, which were presented by Molina, are likely to strengthen Gilead’s application and perhaps usher in a new era of HIV. Lenacapavir is designed to interrupt various phases of the HIV replication. Many of the current HIV treatment inhibit just one phase of viral replication.

Upon enrollment in the CAPELLA trial, patients continued taking treatment they stopped responding to and were randomized to receive either oral lenacapavir or placebo for 14 days. Following those two weeks, patients entered the maintenance part of the study, receiving subcutaneous injections of lenacapavir every six months for a year in addition to an optimized background regimen.

The findings from these 36 patients showed that the treatment was also generally well tolerated among the patients, with no patients discontinuing treatment because of adverse events and no reported serious adverse events related to the treatment. The most common adverse events were mild injection-site reactions.

Data from a different phase 2 trial called CALIBRATE trial suggests that lenacapavir may also be eventually become a treatment option for patients with HIV who have yet to be treated, a much larger group than the patients who have stopped responding to the current batch of treatment. Results from CALIBRATE, which were also presented the International AIDS Society Conference, showed that a combination of lenacapavir, given orally and subcutaneously, and the oral emtricitabine-tenofovir alafenamide combination (which Gilead is selling as Descovy) resulted in 94% of the 157 patients achieving viral suppression by 28 weeks.

The CALIBRATE trial results also show that lenacapavir is well tolerated.

Articles

The favorable results could mean a new treatment option for patients with HIV whose disease has not responded to other treatments. They may also be another step toward HIV treatment that doesn’t depend on daily pills.





Gilead Reports Positive Results for Lenacapavir, Semiannual HIV Treatment

s 2020 came to a close with 53 drug approvals, many wondered about 2021, questioning whether the drugs coming out of the pipeline would slow to a trickle. The answer, so far, is no. As of June 22, the FDA had approved 26 treatments compared with 24 at the same date last year.

The year began with the FDA’s emergency use authorization (EUA) on Feb. 27 for the Johnson & Johnson COVID-19 vaccine, the third such EUA after Pfizer received one for its vaccine on Dec. 11, 2020, and Moderna for its vaccine a week later.

But it has been a bumpy road for the J&J vaccine. Its rollout was paused after several cases of a rare disorder involving blood clots were reported. Hopes that the single-shot vaccine would push the vaccination rate up and thereby help the country achieve herd immunity have failed.

Still, as this issue went to press, the pandemic picture was brightening in the U.S. Just over 45% of the population was fully vaccinated, and the seven-day average of new cases of COVID-19 had dropped to just over 10,000, which is 20 times lower than the seven-day average of over 200,000 at the beginning of the year.

Despite concerns that drug approvals might lag because FDA resources would be pulled into reviewing COVID-19 vaccines and treatment, the 26 approvals so far this year tell another story. Among these approvals are some that have been long anticipated and others that have faced their fair share of controversy.

Easily the most controversial approval was handed to Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease. On June 7, the monoclonal antibody became the first Alzheimer’s treatment approved in nearly two decades and the first that targets the beta-amyloid deposits believed by many to play a causative role in the disease. Aduhelm does not reverse Alzheimer’s but, according to the data on which the approval was based, may slow the rate of cognitive decline.

The approval by itself is significant because millions of Americans with Alzheimer’s may be prescribed the drug. But it may also send a fresh signal that beta-amyloid is a good target for Alzheimer’s treatment. Doubts about treating Alzheimer’s by reducing beta-amyloid deposits in the brain had started to creep in as other treatments that focused on beta-amyloid faltered in later-stage clinical trials.

However, in recent news, the FDA modified the recommended use, limiting it to patients with early-stage symptoms of Alzheimer's. As of July 9, FDA Acting Commissioner, Janet Woodcock, 

 of doctors within the FDA who met with the makers of Aduhelm before its recent approval.

In a letter made public to the Office of Inspector General of the Department of Health and Human Services, Woodcock wrote, "There continue to be concerns raised, however, regarding contacts between representatives from Biogen and FDA during the review process, including some that may have occurred outside of the formal correspondence process,” she wrote. “To the extent these concerns could undermine the public’s confidence in FDA’s decision, I believe that it is critical that the events at issue be reviewed by an independent body such as the Office of the Inspector General in order to determine whether any interactions that occurred between Biogen and the FDA review staff were inconsistent with FDA policies and procedures.”

The monoclonal antibody’s fate was unclear until the approval was announced. In 2019, Biogen and Eisai, which co-developed the drug, terminated two late-stage trials for the drug after an independent data monitoring committee determined that the treatment was unlikely to be successful. Based on re-analysis of the data from one of those trials, known as the EMERGE trial, the companies reversed course and applied for approval. 

At the end of 2020, FDA staffers indicated they backed approval of the drug, but a panel of outside experts, the Peripheral and Central Nervous System Drugs Advisory Committee, effectively voted against approval. Three members of that committee have resigned to protest the FDA approval. Many are questioning the $56,000 price tag, which surpasses expectations and the Institute for Clinical and Economic Review’s cost-effectiveness price range of $11,000 to $23,100 if only the results from the favorable EMERGE trial are used. The FDA used the accelerated approval pathway to approve Aduhelm, which means Biogen must conduct a confirmatory clinical trial. Advisory committee members have told journalists that the FDA didn’t tell them about this possibility and that it occurred late in the process. If the positive results from the EMERGE trial don’t hold in the confirmatory trial, then the FDA could pull back its approval.

An increasing number of cancer drugs, particularly those for non-small cell lung cancer, target mutations. But attempts to target mutations to the KRAS gene, which are among the most common, have failed and KRAS was deemed as possibly being “undruggable.” That changed on

May 28 with FDA’s approval of Amgen’s Lumakras (sotorasib). “The FDA approval of Lumakras is a breakthrough moment for patients with KRAS G12C-mutated non-small cell lung cancer because there is now a targeted therapy for this common, but previously elusive, mutation,” said David M. Reese, M.D., executive vice president of research and development at Amgen, in a press release when the drug received approval.

The approval stems from phase 2 trial data of 124 patients who received the treatment, 36% of whom had at least a 30% decrease in tumor size and 81% of whom responded positively to the treatment. Data presented at the American Society of Clinical Oncology’s annual meeting and reported simultaneously in 

 show that Lumakras may be especially effective in patients whose tumors have a co-mutation in the STK11 gene. Lumakras, which is taken daily as a pill, is being studied in a phase 3 trial, which will determine how the treatment shapes up against docetaxel.

At the same time, Amgen is testing a lower dose of Lumakras, resulting in some speculation about whether there were safety concerns from the FDA as it reviewed the drug. Amgen also faces questions regarding Lumakras’ $17,900 monthly price tag.

Another major development during the first half of the year was the FDA’s approval of Bristol Myers Squibb’s and Bluebird bio’s Abecma (idecabtagene vicleucel) for the treatment of multiple myeloma on March 26. Abecma is a chimeric antigen receptor (CAR)-T cell therapy, and prior to this OK, the indications had been limited to acute lymphoblastic leukemia and several different types of lymphoma.

Abecma is approved for patients with relapsed or refractory multiple myeloma who have already received four previous treatments. In a phase 2 trial, the treatment was evaluated in 128 patients who had received at least three prior treatments. After 13.2 months, nearly 3 in 4 patients responded to treatment, and 1 in 3 had a complete response or better.

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

Not in recent memory has an FDA approval stirred up so much controversy as the agency’s OK of Aduhelm, Biogen’s Alzheimer’s treatment.

2021 Starts Off Strong — and Controversial 

Thanks to decades of research, new treatments for muscular dystrophy that address the disease at the generic level may soon change the course of the disease and help more people.

Muscular dystrophy is a rare group of genetic disorders that cause muscles to waste away over time, creating an inability to move and making everyday tasks difficult, depleting quality of life, and causing early death. The disorders are caused by a defective gene located on the X chromosome that controls production of dystrophin, a protein complex found in muscle fibers.

The most common form of muscular dystrophy is Duchenne muscular dystrophy (DMD), typically seen in boys. Other forms include Becker muscular dystrophy, which is similar to DMD but milder, and limb-girdle muscular dystrophy, which affects the shoulder and pelvic muscles.

Until recently, managing symptoms was the only approach to muscular dystrophy; for example, using corticosteroids that can help strengthen muscle and slow the disease. But there are risks to long-term use of corticosteroids, including weakening of bone tissue that increases the risk of fractures.

Now several pharmaceutical companies are developing gene therapy for muscular dystrophy. Results have been mixed. Earlier this year, Sarepta Therapeutics, a biotech company headquartered in Cambridge, Massachusetts, that focuses on genetic medicine for disorders like DMD, saw its stock price drop in half after it revealed that its investigational gene therapy for DMD, SRP-9001, fell short of its primary end point in a midstage trial. Sarepta attributed these results to differences in fitness among the patients included in the study, and the company released results in May that were more promising.

Sarepta has three products marketed for the treatment of DMD: Exondys 51 (eteplirsen), Vyondys 53 (golodirsen) and Amondys 45 (casimersen). These exon-skipping therapies are indicated for treatment if certain mutations are present and are designed to increase the production of dystrophin. Sarepta also hopes to regain its muscular dystrophy pipeline momentum with a gene therapy for limb-girdle muscular dystrophy, which has no approved treatments.

Pfizer is also looking to make headway in DMD with its gene therapy, fordadistrogene movaparvovec. The company has a phase 3 trial underway and plans to enroll patients across 15 countries. The FDA is addressing outstanding questions regarding the investigational new drug application, says Nicole Kjesbo, Pharm.D., leader of the pipeline team at Prime Therapeutics, a PBM headquartered in Eagan, Minnesota.

Another gene therapy for DMD is under development by Genethon, a French gene therapy company, says Kjesbo. In April, the first patient was dosed with Genethon’s investigational treatment, GNT 0004. Solid Biosciences, a Cambridge, Massachusetts, biotech company, also has a gene therapy candidate for DMD in early-stage trials.

Several companies have therapies for muscular dystrophy in the pipeline that are not gene therapies:

Taiho Pharmaceutical, a Japanese company, has started a phase 3 trial of its oral treatment, pizuglanstat, which is designed to dampen the inflammatory response in the muscles of DMD patients.

Italfarmaco, an Italian company, is testing how well givinostat, an oral treatment, promotes muscle repair in DMD.

FibroGen, headquartered in San Francisco, is testing pamrevlumab, a monoclonal antibody that inhibits connective tissue growth factor in patients with several different illnesses, including DMD. 

is a freelance medical writer based in Jersey City, New Jersey.

The jury is still out. Several companies have high hopes for candidates under development.

Will Gene Therapy Change the Treatment of Muscular Dystrophy?

A potential new generation of treatments for hemophilia may build on the progress made in treating the condition, which affects approximately 400 infants born each year, by reducing the burden that treatment can have on patients’ quality of life.

Hemophilia is a rare, genetic disorder in which a person’s blood does not clot normally, resulting in spontaneous bleeding internally and excessive bleeding after injury or surgery. The condition is more common in males than females, affecting 1 in 5,000 male births.

The condition may result in chronic joint disease from repeated bleeding into the joints, neurological damage and damage to other organ systems. Hemophilia can also lead to quality-of-life issues, including psychological and social issues.

The goal of treatment typically focuses on preventing bleeding. For patients with hemophilia A, the most common type of hemophilia, the inability of the blood to clot is caused by a shortage of a protein called factor VIII. Treatments focus on factor VIII replacement, which helps the blood clot. Thanks to the class of treatment, people with hemophilia A now live nearly as long as people without the condition.

However, there is still room for improvement in hemophilia treatment because of the relatively short half-life — a measurement of how long a drug will work based on the time it takes for the amount of the drug in your body to be reduced by half — of traditional factor VIII treatments. The shorter a drug’s half-life, the more often it needs to be administered.

With traditional factor VIII replacement options, the half-life life ranges from 15 to 19 hours, so patients need to get treatment about every other day. Factor VIII is administered intravenously, so frequent administration has a major effect on the quality of life of patients.

One of the goals of the newer hemophilia A treatments is to lengthen the time between infusions. The newer treatments include:

Biogen’s Eloctate, or antihemophilic factor (recombinant) Fc fusion protein, which in 2014 became the first approved treatment of its kind for adults and children with hemophilia A.

Novo Nordisk’s Esperoct, or antihemophilic factor (recombinant) glycopegylated-exei, which the FDA approved in 2019 for adults and children with hemophilia A.

Bayer’s Jivi, or antihemophilic factor (recombinant) PEGylated-

auci, which was approved in 2018. Long-term results from a phase 3 trial of the treatment were recently released, confirming that the treatment safely prevents bleeds in young boys (under 12 years old).

An even newer generation of factor VIII replacements is aimed at further cutting the number of infusions needed. These treatments have a half-life up to four times that of traditional replacement therapies, so patients only need to be treated once a week.

Sanofi is currently recruiting patients for a phase 3 trial of its experimental treatment, provisionally named BIVV001, which is a fusion of several blood-clotting proteins and a protein polymer, XTEN, that extends the half-lives of therapeutic proteins. Although it remains to be confirmed how well the treatment works, positive results from a phase 1-2a open-label trial were reported in the 

 last year. The small, industry-sponsored study enrolled 16 men with severe hemophilia A who were treated with a single dose of BIVV001.

Other factor VIII products in development include CSL626 from CSL Behring, a biotech company headquartered in suburban Philadelphia, and OCTA101 from Octapharma, a Swiss company that focuses on products made from human plasma.

Longer half-lives mean less frequent administration and improved quality of life. 

Jaime Rosenberg

Articles

Gilead Reports Positive Results for Lenacapavir, Semiannual HIV Treatment

2021 Starts Off Strong — and Controversial

Will Gene Therapy Change the Treatment of Muscular Dystrophy?

New Hemophilia Treatments Look to Cut Number of Infusions