Orphan Drug Act Boosted Rare Disease Therapies, But Access is Uneven

 Nearly 600 orphan products have been approved by the U.S. Food and Drug Administration (FDA) since the passage of the Orphan Drug Act, many of which would not have been developed otherwise, according to a new report commissioned by patient advocacy group National Organization for Rare Disorders (NORD).

But the analysis by health care data firm Avalere notes that patent protections–even beyond the orphan drug exclusivity granted in legislation–have limited generic or biosimilar competitors to only 81 products.

The Orphan Drug Act passed in 1983 and granted tax credits, subsidies and fee waivers for rare disease drug development in areas of unmet need. It also guaranteed seven years of market exclusivity following approval, longer than the five years typical for most new chemical entities.

At the time, the FDA had approved only 38 drugs, despite the fact there are about 7,000 rare diseases affecting 25 million patients. The FDA has since approved another 599, but more than 90% of rare diseases still have no approved therapies.

"More than 9 out of 10 orphan products on the market today would never have been developed without the Orphan Drug Act,” said Peter Saltonstall, President and CEO of NORD.

But given the remaining patient need, he added, government action was required to provide a framework that would balance incentives to innovate with reasonable competition.

Even where drugs are approved, it is unclear how many patients are able to access them. According to the report, the cost for payers remains an issue because most orphan drugs do not face generic or biosimilar competition: of the 552 orphan drugs still on the market, only 14% faced competition.

One reason is the seven-year exclusivity period, which prevented competition for 61 orphan drugs. And about a quarter of orphan drugs are approved for two or more indications—great for patients, but stalling full on-label market access for generic or biosimilar competitors.

But a bigger factor is the life of the patent. According to Avalere, 125 orphan drugs still have patent exclusivity even though their market exclusivity has lapsed. (Another 208 are still under both market and patent exclusivity.) And about a fifth of orphan products have active patent protection beyond the 20-year exclusivity guaranteed after the patent was filed.

Of the 158 orphan drugs with expired patent and market exclusivity periods, half have generic or biosimilar competition.

https://www.biospace.com/article/report-orphan-drug-act-boosted-rare-disease-therapies-but-access-is-uneven/

Is the FDA Getting Tougher on Drug Applications?

 It’s already been reported that the U.S. Food and Drug Administration (FDA) is running an industry-wide evaluation of its accelerated approvals. These approvals were typically granted for drugs with a high unmet need and require the companies to conduct post-marketing clinical trials to determine if, in fact, the drugs are as effective as they appeared to be in earlier trials.

Now there appears to be some evidence that the agency is cracking down in general, although there’s debate among analysts about what exactly is going on.

Some analysts believe that a number of rescinded accelerated approvals and unexpected rejections is simply a short-term slowdown, possibly associated with overwhelming COVID-19-related work and the lack of a permanent commissioner. In early March, six former FDA commissioners urged President Biden to nominate a permanent agency head. The interim commissioner is Janet Woodcock, a 36-year-veteran of the agency, who many in the industry think should be made permanent commissioner.

Other analysts think that the apparently tougher stance of the agency is just a swing toward a more cautious approach after a number of years of being more industry-friendly.

“The relatively predictable regulatory outcomes of the last four or five years may not be as predictable going forward, which of course increases the perceived riskiness of the industry,” said Geoffrey Porges, analyst with SVB Leerink.

On its part, the FDA has not announced a policy shift and told Barron’s that it was not processing drug applications more slowly during the pandemic.

In recent weeks, there have been a number of failed confirmation trials, forcing the companies to withdraw their products for those indications. On March 1, Merck announced it had voluntarily withdrawn the U.S. indication for Keytruda for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other previous line of therapy. This was done in consultation with the FDA. The company notes that this decision has no effect on other indications for Keytruda.

A week earlier, AstraZeneca announced it was withdrawing its checkpoint inhibitor Imfinzi in bladder cancer over a similar response. Given the number of accelerated approvals in recent years, others are expected to follow.

The Imfinzi accelerated approval was for advanced bladder cancer with high PD-1 levels or in patients regardless of PD-1 status, and was to be confirmed by the DANUBE trial, but failed to meet the overall survival endpoints compared to standard of care.

For patients with extensive-stage small cell lung cancer, Imfinzi is approved as a first line treatment, based on OS data from the Phase III CASPIAN clinical trial.

The checkpoint inhibitor received accelerated approval for this indication in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). The deal with the FDA was that the approval was contingent on completing a post-marketing evaluation proving Keytruda was superior to other products in extending overall survival (OS).

On January 2020, KEYNOTE-604, the confirmatory Phase III trial, hit one of the dual primary endpoints, progression-free survival (PFS), but didn’t reach statistical significance for the other primary endpoint of OS.

“The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past five years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments,” said Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Keytruda remains a foundational treatment for certain patients with metastatic non-small cell lung cancer. We will continue to rigorously evaluate the benefits of Keytruda in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives.”

Some analysts are trying to judge FDA’s mood based on whether it approves Biogen’s aducanumab for Alzheimer’s in June. In many ways, that’s a bizarre thing to try to evaluate the agency’s overall approach, because it’s such a dramatic outlier. It was originally abandoned due to futility in March 2019, then a few months later, Biogen and development partner Eisai said the trial had met its primary endpoint in at least one cohort.

Biogen presented the findings in the final data analysis in a December 2019 conference, and although there was still some skepticism about the overall data, it did appear to be enough to file for a BLA and the company planned to do so in the second quarter of 2020.

What they presented was that the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen said the data from a subset of patients that received a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation and language, as well as benefits on activities of daily living.

There have been delays in the submission, at least partly due to the COVID-19 pandemic, but also related to FDA’s request for more data.

Then, in November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee slammed the drug submission, voting 1 yes, 8 no and 2 uncertain on the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?” It also voted 0 yes, 7 no and 4 uncertain on whether Study 103 (PRIME) supported the effectiveness of the drug. Again and again, the committee voted against the drug.

Andrew Baum, global head of healthcare research at Citigroup, is one of the analysts who thinks the Biogen application could be a bellwether for how the FDA is cracking down.

“That will tell you whether, in the face of an overtly negative independent advisory panel, the FDA is willing to overrule,” he said.

Barron’s cites several delays, including FDA deciding in early March to convene an advisory committee over FibroGen’s Roxadustat less than a month before the target action date, delayed decisions on drug applications from AbbVie and Kadmon Holdings, and refusing to accept a filing from Novo Nordisk.

Porges went so far as to downgrade six biopharma stocks this week, including GlaxoSmithKline and Alexion Pharmaceuticals, in a note to investors about “emerging concerns about the industry’s operating environment.”

However, Mark Breidenbach, an analyst at Oppenheimer, is more inclined to believe the agency is just extremely busy. “It’s the unfortunate reality of having a zillion applications, all focused on COVID-related stuff, utterly swamping the agency.”

https://www.biospace.com/article/fda-appears-to-be-getting-tougher-on-drug-applications/

SARS-CoV-2 circulated undetected months before 1st COVID-19 cases in Wuhan, China: study

 Using molecular dating tools and epidemiological simulations, researchers at University of California San Diego School of Medicine, with colleagues at the University of Arizona and Illumina, Inc., estimate that the SARS-CoV-2 virus was likely circulating undetected for at most two months before the first human cases of COVID-19 were described in Wuhan, China in late-December 2019.

Writing in the March 18, 2021 online issue of Science, they also note that their simulations suggest that the mutating virus dies out naturally more than three-quarters of the time without causing an epidemic.

"Our study was designed to answer the question of how long could SARS-CoV-2 have circulated in China before it was discovered," said senior author Joel O. Wertheim, Ph.D., associate professor in the Division of Infectious Diseases and Global Public Health at UC San Diego School of Medicine.

"To answer this question, we combined three important pieces of information: a detailed understanding of how SARS-CoV-2 spread in Wuhan before the lockdown, the genetic diversity of the virus in China and reports of the earliest cases of COVID-19 in China. By combining these disparate lines of evidence, we were able to put an upper limit of mid-October 2019 for when SARS-CoV-2 started circulating in Hubei province."

Cases of COVID-19 were first reported in late-December 2019 in Wuhan, located in the Hubei province of central China. The virus quickly spread beyond Hubei. Chinese authorities cordoned off the region and implemented mitigation measures nationwide. By April 2020, local transmission of the virus was under control but, by then, COVID-19 was pandemic with more than 100 countries reporting cases.

SARS-CoV-2 is a zoonotic coronavirus, believed to have jumped from an unknown animal host to humans. Numerous efforts have been made to identify when the virus first began spreading among humans, based on investigations of early-diagnosed cases of COVID-19. The first cluster of cases—and the earliest sequenced SARS-CoV-2 genomes—were associated with the Huanan Seafood Wholesale Market, but study authors say the market cluster is unlikely to have marked the beginning of the pandemic because the earliest documented COVID-19 cases had no connection to the market.

Regional newspaper reports suggest COVID-19 diagnoses in Hubei date back to at least November 17, 2019, suggesting the virus was already actively circulating when Chinese authorities enacted public health measures.

In the new study, researchers used molecular clock evolutionary analyses to try to home in on when the first, or index, case of SARS-CoV-2 occurred. "Molecular clock" is a term for a technique that uses the mutation rate of genes to deduce when two or more life forms diverged—in this case, when the common ancestor of all variants of SARS-CoV-2 existed, estimated in this study to as early as mid-November 2019.

Molecular dating of the most recent common ancestor is often taken to be synonymous with the index case of an emerging disease. However, said co-author Michael Worobey, Ph.D., professor of ecology and evolutionary biology at University of Arizona: "The index case can conceivably predate the common ancestor—the actual first case of this outbreak may have occurred days, weeks or even many months before the estimated common ancestor. Determining the length of that 'phylogenetic fuse' was at the heart of our investigation."

Based on this work, the researchers estimate that the median number of persons infected with SARS-CoV-2 in China was less than one until November 4, 2019. Thirteen days later, it was four individuals, and just nine on December 1, 2019. The first hospitalizations in Wuhan with a condition later identified as COVID-19 occurred in mid-December.

Study authors used a variety of analytical tools to model how the SARS-CoV-2 virus may have behaved during the initial outbreak and early days of the pandemic when it was largely an unknown entity and the scope of the public health threat not yet fully realized.

These tools included epidemic simulations based on the virus's known biology, such as its transmissibility and other factors. In just 29.7 percent of these simulations was the virus able to create self-sustaining epidemics. In the other 70.3 percent, the virus infected relatively few persons before dying out. The average failed epidemic ended just eight days after the index case.

"Typically, scientists use the viral genetic diversity to get the timing of when a virus started to spread," said Wertheim. "Our study added a crucial layer on top of this approach by modeling how long the virus could have circulated before giving rise to the observed genetic diversity.

"Our approach yielded some surprising results. We saw that over two-thirds of the epidemics we attempted to simulate went extinct. That means that if we could go back in time and repeat 2019 one hundred times, two out of three times, COVID-19 would have fizzled out on its own without igniting a pandemic. This finding supports the notion that humans are constantly being bombarded with zoonotic pathogens."

Wertheim noted that even as SARS-CoV-2 was circulating in China in the fall of 2019, the researchers' model suggests it was doing so at low levels until at least December of that year.

"Given that, it's hard to reconcile these low levels of virus in China with claims of infections in Europe and the U.S. at the same time," Wertheim said. "I am quite skeptical of claims of COVID-19 outside China at that time."

The original strain of SARS-CoV-2 became epidemic, the authors write, because it was widely dispersed, which favors persistence, and because it thrived in urban areas where transmission was easier. In simulated epidemics involving less dense rural communities, epidemics went extinct 94.5 to 99.6 percent of the time.

The virus has since mutated multiple times, with a number of variants becoming more transmissible.

"Pandemic surveillance wasn't prepared for a virus like SARS-CoV-2," Wertheim said. "We were looking for the next SARS or MERS, something that killed people at a high rate, but in hindsight, we see how a highly transmissible virus with a modest mortality rate can also lay the world low."

More information: Jonathan Pekar et al, Timing the SARS-CoV-2 index case in Hubei province, Science (2021). DOI: 10.1126/science.abf8003

https://medicalxpress.com/news/2021-03-sars-cov-circulated-undetected-months-covid-.html

Carcinogen Benzene Found in Multiple Hand Sanitizer Brands

 Online pharmacy Valisure is sounding the alarm over what it says are contaminated batches of a pandemic staple.

The New Haven, Connecticut-based company announced Wednesday that it had detected benzene, a known human carcinogen, in several batches across multiple brands of hand sanitizer.

Valisure submitted a citizen petition to the FDA, asking the agency to request an immediate recall of the affected batches and update guidance to include an exposure limit for benzene. The FDA regulates hand sanitizer as a drug product.

"The presence of benzene, a known human carcinogen, and multiple other contaminants, in products widely recommended for the prevention of spreading the SARS-CoV-2 virus causing COVID-19 and regularly used by adults and children in large volumes makes these findings especially troubling," the company wrote in its citizen petition.

That's in part because the National Institute for Occupational Safety and Health lists "'inhalation, skin absorption, ingestion, skin and/or eye contact'" as exposure routes for benzene, the company wrote.

Valisure -- which was founded in 2015 on the premise of independently testing the medications it sells -- noted that the FDA has said benzene should not be used in drug products because of its toxicity. (Benzene is a widely used industrial solvent, is present in substances such as gasoline, cigarette smoke, and forest fires, and is also a feedstock for other chemicals.)

However, during the current public health emergency, FDA has set an interim limit of 2 parts per million for the chemical only in liquid hand sanitizers.

Valisure said a good portion of the batches of hand sanitizer it tested missed FDA's mark.

The company analyzed 260 unique batches of hand sanitizer from 168 brands, according to its citizen petition. Of those batches, 44 -- or 17% -- contained benzene levels of at least 0.1 ppm, the company's testing found. Twenty-one batches (8%) -- which included liquid and gel hand sanitizers -- contained benzene above the 2 ppm interim limit. The highest level of benzene detected was 16.1 ppm, more than eight times the limit.

Valisure noted in its FDA petition that, in addition to benzene, it also found sanitizer batches with high levels of methanol and acetaldehyde -- categorized by leading health organizations as "possibly carcinogenic to humans." The FDA has issued warnings about methanol in hand sanitizers.

In the general course of business, Valisure regularly checks thousands of products, said David Light, the company's founder and CEO. Another member of the team recently suggested adding benzene to the list of chemicals Valisure tests for since it's a general area of concern and the company continues to expand what it looks for in drugs.

Given the known toxicity of benzene, Light said he wasn't expecting to find much.

However, he said, "As we've been scanning more hand sanitizer-type products, we started seeing some signals there." As a result, the company decided to undertake what Light called a broader market sweep.

Light said that Valisure's hand sanitizer findings indicate contamination with benzene is "a batch-to-batch problem." At this point, he said the company can't specify whether buying a certain brand of hand sanitizer over another prevents the problem from affecting purchasers.

It's hard to know whether the presence of benzene in these products emerged before the pandemic, Light said. As part of addressing that question, the company has opened a crowdsourcing study for hand sanitizer through which individuals and organizations can send their own products or packages to be tested.

There may be things to be learned about distribution or expiration dates, Light said. "I think there's going to be a lot more information that comes out as time goes on."

Valisure said it's also asking the FDA to further investigate batches of hand sanitizer that, in addition to containing benzene, are inconsistent with agency guidance not to add inactive ingredients -- such as those that improve smell, taste, or appearance -- that can increase the risk of ingestion by children.

The FDA said in a statement to MedPage Today that it "continues to test hand sanitizer products and proactively work with companies, when appropriate, to recall products and encourage retailers to remove products from store shelves and online marketplaces when quality issues arise."

The agency added that it "reminds manufacturers, distributors, repackagers and importers they are responsible for the quality of their products and urges manufacturers to test their ingredients to ensure they meet specifications and are free from harmful contamination."

The FDA is currently reviewing Valisure's petition on benzene.

Previously, Valisure has identified quality issues that led to global recalls of the antacid medication ranitidine and the diabetes drug metformin.

https://www.medpagetoday.com/special-reports/exclusives/91806

How We Should Approach Coronavirus Variant Tracking

 COVID-19 daily cases have plummeted 65% over the last five weeks, mostly because natural immunity from prior infection is much higher than many experts predicted. Augmenting that community immunity are vaccines, which are now being delivered at a rate of approximately 1.7 million per day. By April, the rate of new coronavirus infections in the U.S. is likely to be very low.

But a looming threat -- variants -- means it's too early for us to breathe a sigh of relief. Until this point, reinfections have been rare during the pandemic. But the Brazilian strain of COVID-19 has demonstrated both laboratory and clinical evidence of having partially mutated around natural and vaccinated immunity. The Brazilian and South African variants have a mutation of the receptor-binding domain, which may partially or completely evade testing or antibody therapy. There may also be variants that have yet to be described but may emerge in the coming weeks to months.

Genetic sequencing allows us to understand the unique clinical characteristics of new variants and design a modified vaccine to prevent their transmission next fall. We're going to be living with COVID -19 for a long time. It's like the four other coronaviruses that have circulated seasonally and make up approximately 25% of the cases of the common cold. It appears that COVID-19 has become the fifth -- and the deadliest.

The U.S. had been sampling approximately 250 infections per week and more recently, the number has increased to 4,000 infections per week. But as we hunt for new variants, we should sequence wisely.

In addition to random sampling, we should order gene sequencing for all COVID-19 cases that meet any of the following criteria:

1. Any COVID-19 re-infection
2. Any COVID-19 death in a healthy person under age 50
3. Any COVID-19 infection acquired after recent travel overseas
4. Any COVID-19 infection that tested negative and later tested positive during the same sickness
5. Any COVID-19 infection in which antibody therapy was ineffective and the patient's condition worsened
6. Any atypical COVID-19 infection

Given the risk of the unknown with new variants, any patient meeting these criteria should also undergo detailed contact tracing. We must be on the lookout. Selective sequencing in addition to random sampling for surveillance will also help us understand the prevalence and clinical manifestations of new variants.

Testing for COVID-19 last year was embarrassingly late to market and woefully inadequate for much of the spring and summer. But we can do sequencing right. We should invest in sequencing on a national level. And at the bedside, whenever possible, physicians should order genetic sequencing on all atypical cases and unusual presentations, which could be an early detection system for a future epidemic.

Marty Makary MD, MPH, is editor-in-chief of MedPage Today as well as professor of surgery and health policy at the Johns Hopkins University School of Medicine and author of The Price We Pay: What Broke American Health Care -- and How to Fix It.

https://www.medpagetoday.com/blogs/marty-makary/91237

NIAID Launches Trial to Assess Post-Vax COVID Transmission Risk

 Thousands of college students participating in a new trial called PreventCOVIDU will help determine how well COVID-19 vaccines diminish risk of transmitting the infection, officials said Friday.

That the vaccines are highly effective at preventing symptomatic illness is well established.

"But the prevailing question is, when these people get infected, how often is that, if they're asymptomatic, how much virus do they have in their nose?" said Anthony Fauci, MD, President Biden's chief medical advisor and director of the National Institute of Allergy and Infectious Diseases, during a White House briefing. "And do they transmit it to people who are their close contacts?"

The open-label randomized trial, which began on Thursday, will test whether vaccine prevents both infection and transmission of SARS-CoV-2 among college students, and will "help inform science-based decisions about mask use and about social distancing post-vaccination," Fauci added.

The NIH-funded study will include 12,000 college students ages 18 to 26 from more than 20 universities, and is expected to last 5 months, Fauci said. One group of 6,000 students will receive their first dose of the Moderna vaccine immediately. The others will serve as controls and will receive their vaccine 4 months later.

All participants will ultimately receive the usual two doses.

Participants will swab their noses daily for SARS-CoV-2 infection, provide blood samples periodically, and complete surveys through an electronic diary app. They will also be asked to follow their university's SARS-CoV-2 protocols and get tested twice each week, according to the study's website.

Anyone who tests positive will be asked to follow additional protocols.

Another 25,000 individuals whom participants name as "close contacts" -- for example, roommates or co-workers -- will also provide blood samples to the researchers, take daily nose swabs for 2 weeks, and answer weekly questionnaires (if they agree to participate, of course).

"The degree of transmission from vaccinated individuals will be determined by the infection rate in the close contacts," Fauci explained.

The study website indicates that participants will be paid for the daily swab collection, with the precise amount varying among locations and other factors. These details will be reviewed during the informed consent process.

Exclusion criteria for the trial include:

• Self-reported known history of SARS-CoV-2 infection
• Blood products, systemic immunoglobulins, or monoclonal antibodies (including against SARS-CoV-2) received within 90 days before first vaccination
• Investigational research agents received within 30 days before first vaccination

Students who've already received a COVID vaccine dose, have taken an immunosuppressive medication within 168 days, or have "clinically significant medical conditions" are ineligible.

The study was designed and will be overseen by researchers at the COVID-19 Prevention Network (CoVPN), whose headquarters are located at the "Fred Hutch" cancer center in Seattle.

An article about the study posted on the Fred Hutch website says that, while the study will use the Moderna vaccine, results should apply as well to the similar mRNA product developed by Pfizer and BioNTech.

Generalizability to other vaccines, such as the adenovirus-based products from AstraZeneca and Johnson & Johnson, or those in development using synthetic protein antigens, is more speculative. However, most people in the U.S. are receiving the mRNA vaccines.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/91832

Proqr hopes to usher in a new ophthalmic therapy

 Mixed mid-stage data on Proqr’s exon skipper QR-421a in the rare ophthalmic disorder Usher syndrome were released early on Wednesday morning to widespread apathy. Yesterday, however, the company’s stock shot up 61%. It is not clear why this reaction was delayed. 

Neither is it clear that it was justified. The phase 1/2 data are apparently enough for Proqr to push ahead with pivotal studies, but they are not wildly positive, and the number of patients is small. There is one thing in the company’s favour, however: should phase 3 show a more definite benefit, Proqr looks likely to have the Usher’s market to itself for some time. 

The phase 1/2 Stellar trial saw 14 patients with Usher syndrome and non-syndromic retinitis pigmentosa due to exon 13 mutations in the USH2A gene receive Proqr’s intravitreous antisense oligonucleotide, and six receive a sham injection. Skipping the mutated exon should allow production of a shorter but still functional form of usherin, a protein necessary for the development of the inner ear and retina. 

In the trial subjects with advanced disease the primary measure of efficacy was best corrected visual acuity. In all 14 treated patients a mean benefit of 6.0 letters was seen in the treated compared with untreated eyes 48 weeks after a single injection. In the six with advanced disease the mean benefit in the treated versus untreated eyes was 9.3 letters at week 48.

According to Evercore ISI analysts, a three-line gain on the standard chart used for BCVA is considered clinically meaningful by the FDA. Since there are five letters in each line on the chart, Stellar appears to have missed this threshold. It is close to meeting the EMA’s requirement for meaningfulness, however, at least in the advanced patient cohort: the EU agency has set this at a gain of two lines. 

Sirius business

In early to moderate patients Stellar’s primary efficacy goal was measurement of visual fields by static perimetry – a way of assessing vision in the peripheral retina, measured in decibels. In these eight patients, up to a mean of 13 retinal locations in the treated eyes improved by at least 7dB, versus seven locations for the untreated eyes at the same time point.

Evercore ISI analysts state that an increase of at least 7dB in five locations is considered clinically meaningful, and a registerable endpoint. The eyes treated with QR-421a hit this target; unfortunately, so did the untreated eyes. There were no serious adverse events and no inflammation in Stellar. 

Proqr by the end of the year plans to put QR-421a into two parallel pivotal phase 2/3 trials: Celeste, in patients with early to moderate disease, and Sirius, in advanced patients.

Both trials are expected to last for two years, meaning data are unlikely to appear before 2024. But Proqr is still in a dominant position in Usher. Around 16,000 people worldwide have the exon 13 mutation form of the disease, and there are no treatments.

The competition

The only other project in active clinical development specifically for Usher syndrome – excluding lapsed trials, natural history studies and academic work – appears to be a form of N-acetylcysteine amide under investigation by the Texan group Nacuity Pharmaceuticals. The Slo-RP trial compares an oral therapy, NPI-001, versus placebo in 48 patients with retinitis pigmentosa associated with Usher syndrome.

The endpoint, change in retinal sensitivity assessed by microperimetry, will be evaluated after two years’ treatment, and data could come in late 2023 – just before Proqr’s pivotal data might emerge.

A project known as UshStat or SAR421869, licensed by Sanofi from Oxford Biomedica, was discontinued two years ago while still in phase 2 (Sanofi does a spring clean, February 7, 2019).

There is some preclinical activity: Editas has a programme in Usher syndrome 2a, EDIT-102, which uses Crispr to edit exon 13 to restore healthy USH2A protein expression. It is not clear when human trials might start. Proqr has a clear runway – but phase 3 findings might have to be more convincing than Stellar.

The Usher syndrome landscape
Project	Mechanism	Company	Trial details	N	Data
Phase 2/3
QR-421a	Exon-skipping oligonucleotide	Proqr	Sirius: sham-controlled, 24mth, multiple-dose study in advanced Usher and nsRP due to USH2A exon 13 mutations	100	Expected 2024
QR-421a	Exon-skipping oligonucleotide	Proqr	Celeste: sham-controlled, 24-month, multiple-dose study in early-moderate Usher and nsRP due to USH2A exon 13 mutations	100	Expected 2024
Phase 1/2
QR-421a	Exon-skipping oligonucleotide	Proqr	Stellar: sham-controlled trial of QR-421a in subjects with Usher and nsRP due to USH2A exon 13 mutations	18	Mixed results
NPI-001	Antioxidant	Nacuity	Slo-RP: placebo-controlled trial in RP associated with Usher syndrome	48	Expected 2023
Preclinical
EDIT-102	Crispr therapeutic	Editas	-	-	-
nsRP = non-syndromic retinitis pigmentosa. Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/trial-results/proqr-hopes-usherin-new-ophthalmic-therapy