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OrphAI Therapeutics&#8217; experimental therapy <a href="https://www.orphai-therapeutics.com/ait-101-product-page">AIT-101</a> has been awarded orphan drug status in the European Union for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), following a similar designation granted in the U.S. last year.
In Europe, orphan drug status is given to medicines designed to treat life-threatening or chronically debilitating conditions affecting fewer than five in every 10,000 people. It provides companies with a range of benefits, including assistance with trial protocols, reduced regulatory fees, and 10 years of market exclusivity if the treatment is ultimately approved.
Similar benefits are awarded in the U.S., where the therapy received such a designation last June from the U.S. Food and Drug Administration (FDA), though the market exclusivity period is seven years.
“OrphAI Therapeutics now has orphan designation for AIT-101 both in the US and the EU for the treatment of ALS, an important step toward bringing the drug to patients suffering from this neurodegenerative disorder,” Brigette Roberts, MD, <a href="https://www.orphai-therapeutics.com/">OrphAI</a>’s CEO and director, said in a <a href="https://www.globenewswire.com/news-release/2024/02/15/2830145/0/en/OrphAI-Therapeutics-receives-Orphan-Drug-Designation-for-AIT-101-as-a-treatment-for-amyotrophic-lateral-sclerosis-in-the-European-Union.html">company press release</a>.
“We look forward to moving AIT-101 into the next stage of clinical development,&#8221; Roberts added.
[recommended-reading id=83376]
<h3>AIT-101 awarded orphan drug status in US last year</h3>
The molecular mechanisms that <a href="https://alsnewstoday.com/causes-of-als/">cause ALS</a> are not fully understood, but most cases of the progressive disease are marked by the accumulation of toxic TDP-43 clumps in motor neurons — the nerve cells that control voluntary movements and are lost in ALS. These clumps trigger a number of stress responses in cells that ultimately contribute to motor neuron dysfunction and death.
AIT-101, also called LAM-002A or apilimod, is an experimental oral therapy that&#8217;s designed to activate cells&#8217; waste disposal systems. Included in those systems are lysosomes — membrane-bound organelles containing enzymes that break down cellular waste — and autophagy, a cellular process that involves the degradation and recycling of larger cell components that are no longer needed.
By activating these two processes, AIT-101 is expected to help clear the misfolded proteins and toxic protein clumps that contribute to disease progression. The therapy works by inhibiting, or blocking, a protein called PIKfyve.
In preclinical studies, AIT-101 was shown to clear toxic protein clumps and <a href="https://www.nature.com/articles/nm.4490">improve the survival of motor neurons</a> derived from ALS patients. Moreover, the therapy was effective at <a href="https://www.biorxiv.org/content/10.1101/685800v1.full">improving functional deficits</a> in a mouse model of ALS.
Its use &#8220;in relevant animal models has been shown to reverse the pathological [disease-causing] and functional consequences of &#8230; toxic aggregates,&#8221; or clumps, OrphAI notes on its webpage.
AIT-101 was investigated in a recently completed <a href="https://clinicaltrials.gov/study/NCT05163886">Phase 2a clinical trial (NCT05163886)</a> involving 15 adults with ALS caused by mutations in the C9orf72 gene. Such mutations are the most common genetic cause of ALS; the C9orf72 gene carries instructions for a protein of the same name, necessary for the production of lysosomes.
In the trial, participants were randomly assigned to take oral capsules of AIT-101 or a placebo, twice daily, for 12 weeks, or about three months. Then, for the next 12 weeks, all participants received AIT-101.
The trial <a href="https://alsnewstoday.com/news/ait-101-clears-toxic-protein-clumps-early-clinical-trial-als/">met its main goal</a> of showing that AIT-101 was generally safe and well tolerated, and was able to reach the patients’ brains. Moreover, the therapy significantly reduced the levels of toxic protein clumps derived from the mutated C9orf72 gene by 73%, and increased the levels of another marker suggesting the therapy was affecting the PIKfyve protein as expected.
According to the company, AIT-101 is &#8220;the most clinically advanced PIKfyve inhibitor in development.&#8221;

OrphAI’s AIT-101 granted orphan drug status in Europe for ALS

An advisory committee of the European Medicines Agency (EMA) has recommended that Biogen&#8217;s <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) be approved in the European Union under exceptional circumstances to treat adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) associated with SOD1 gene mutations.
The positive opinion from the Committee for Medicinal Products for Human Use, known as CHMP, is based on clinical and biomarker data from the <a href="https://clinicaltrials.gov/study/NCT02623699">Phase 1/2/3 VALOR clinical trial (NCT02623699)</a>, which altogether tested Qalsody in more than 175 patients. Overall, the treatment candidate led to a 60% reduction in blood levels of neurofilament light chain (NfL), a marker of nerve cell damage.
An approval under exceptional circumstances can be recommended for therapies with a positive risk-benefit, but where comprehensive data are unlikely to be obtained given the rarity of the disease. The recommendation now will be reviewed by the European Commission, with a decision expected between April and June.
If approved, Qalsody will become the first therapy authorized in the European Union to target a genetic cause of ALS.
“The CHMP’s positive opinion reinforces the impact Qalsody can have in SOD1-ALS and further demonstrates Biogen’s commitment to address the unmet needs of people living with ALS and neuromuscular diseases,” Priya Singhal, MD, <a href="https://www.biogen.com/">Biogen</a>’s head of development, said in a <a href="https://investors.biogen.com/news-releases/news-release-details/biogens-qalsodyr-tofersen-first-therapy-treat-rare-genetic-form">company press release</a>.
[recommended-reading id=78763]
<h3>Qalsody approved in US in 2023, also for use in adults</h3>
In the U.S., Qalsody early last year was <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">granted conditional approval</a> to treat adults with SOD1-ALS. The U.S. Food and Drug Administration&#8217;s decision also marked the the first conditional approval of a treatment for this form of ALS in that country.
Per the <a href="https://www.biogencdn.com/us/pdfs/qalsody-prescribing-information.pdf">medication&#8217;s label</a>, injections are given monthly into the spinal canal, or intrathecally, following three initial doses given two weeks apart.
Experts welcomed the positive opinion from the CHMP.
“This is a significant milestone for the entire ALS community — for the first time we have a treatment that led to sustained reductions in neurofilament, a marker of [nerve cell] injury and neurodegeneration,” said Philip Van Damme, MD, PhD, professor of neurology and director of the Neuromuscular Reference Center at the University Hospital Leuven, in Belgium.
<a href="https://alsnewstoday.com/als-and-genetics/">Mutations in the SOD1 gene</a> are found in as many as 20% of people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and up to 2% of people with <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>, where there&#8217;s no known family history of the disease. Such mutations result in a toxic form of the SOD1 protein, which is prone to form toxic clumps that accumulate and damage nerve cells.
[quote=&#8221;center&#8221;]This is a significant milestone for the entire ALS community — for the first time we have a treatment that led to sustained reductions in neurofilament, a marker of [nerve cell] injury and neurodegeneration.[/quote]
To produce the SOD1 protein, SOD1&#8216;s genetic code is used to form an intermediate molecule called messenger RNA, or mRNA. The mRNA then is shipped from the nucleus to the cell&#8217;s protein-making machinery, where it is used as a template for making SOD1.
Qalsody belongs to a class of therapies called antisense oligonucleotides (ASOs), and is designed to bind to SOD1&#8216;s mRNA and promote its degradation. That allows it to halt the production of the mutated SOD1 protein. By doing so, the therapy is expected to reduce toxic SOD1 clumps, slow disease progression, and potentially extend survival in SOD1-ALS patients.
[recommended-reading id=83790]
<h3>Treatment found to slow ALS progression in VALOR study</h3>
The three-part VALOR study, started in 2016, investigated Qalsody in a total of 176 ALS patients carrying SOD1 mutations.
In its Phase 1/2 parts, the therapy — then still known as tofersen — was found to be <a href="https://alsnewstoday.com/news/tofersen-safe-appears-to-slow-disease-progression-in-sod1-als-patients-phase-1-2-trial-shows/">generally safe and well tolerated</a> when given in single or multiple ascending doses. It also was shown to have the ability to reduce SOD1 and NfL levels in the spinal fluid.
The Phase 3 part then enrolled 108 patients who were randomly assigned to receive eight intrathecal injections of Qalsody (100 mg), or a placebo, given over six months. The main goal of this part was to assess changes in functional disability among the 60 patients with rapidly progressing ALS, after 28 weeks, or about seven months.
While the trial failed to meet its goal, trends supporting Qalsody were observed in some secondary measures, including muscle strength, quality of life , and lung function. Also, the medication resulted in <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">marked drops</a> in blood NfL levels — by 60% compared with a placebo.
After completing VALOR, participants could enter an <a href="https://clinicaltrials.gov/study/NCT03070119">open-label extension study (NCT03070119)</a>, which is still ongoing, wherein all are receiving Qalsody for up to seven years.
One-year data including the Phase 3 trial and the extension study showed the treatment led to a significant and clinically meaningful slowing of ALS progression. Specifically, those who started on the medication in VALOR had a 6-point decline in ALS Functional Ratings Scale-Revised (ALSFRS-R) scores versus a 9.5-point decline for those who were initially on a placebo.
The most common side effects in Qalsody-treated patients included muscle and joint pain, fatigue, fever, and increased levels of white blood cells and proteins in the spinal fluid.
The therapy now is also being tested in the <a href="https://www.clinicaltrials.gov/study/NCT04856982">ATLAS Phase 3 trial (NCT04856982)</a>. That global study is evaluating whether Qalsody can delay the onset of ALS symptoms in patients with a SOD1 mutation who already show signs of neuronal damage, as defined by elevated NfL levels. It&#8217;s slated to run through 2027.
“We are proud to help pioneer the role of neurofilament in SOD1-ALS clinical trials and are deeply grateful to the people living with SOD1-ALS, their loved ones and study care teams for their dedication to furthering research for the ALS community,” Singhal said.

Committee favors EU approval of Qalsody for adults with SOD1-ALS

An advisory committee of the European Medicines Agency has maintained its recommendation not to approve <a href="https://alsnewstoday.com/amx0035/">AMX0035</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
In its <a href="https://alsnewstoday.com/news/chmp-opposes-approval-amx0035s-als-treatment-europe/">initial assessment issued in June</a>, the Committee for Medicinal Products for Human Use (CHMP) said data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR Phase 2 trial (NCT03127514)</a>, which formed the basis for the application, did not convincingly show that AMX0035 was effective at slowing ALS progression.
<a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a>, the company developing the treatment, then requested a formal re-examination, in which available clinical data were evaluated by a different set of examiners, but this second review process has confirmed the initial opinion.
An official decision on AMX0035 from the European Medicines Agency is now set to be handed down by year&#8217;s end. The regulatory agency is not obligated to abide by the committee’s opinion, but it usually does.
“We are disappointed to learn of this outcome, as it is a further setback for the more than 30,000 people <a href="https://alsnewstoday.com/living-with-als-2/">living with ALS</a> and their loved ones in Europe who have not seen therapeutic progress for this devastating disease in over 25 years,” the patients and carers board of the <a href="https://als.eu/">European Organization for Professionals and Patients with ALS</a> said in a <a href="https://www.businesswire.com/news/home/20231012969323/en/Amylyx-Pharmaceuticals-Receives-Negative-CHMP-Opinion-on-its-Marketing-Authorisation-Application-for-AMX0035-for-the-Treatment-of-ALS-in-the-European-Union-Following-Re-Examination-Process">press release</a>.
[recommended-reading id=86997]
<h3>Other paths to AMX0035&#8217;s approval in Europe being explored</h3>
Meanwhile, the company says it will continue to explore other paths to AMX0035&#8217;s approval in Europe.
The treatment is being evaluated in a larger Phase 3 trial called <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">PHOENIX (NCT05021536)</a>, whose data was not included in the initial application. Pending positive results, Amylyx is planning to submit an application to the European agency as soon as possible.
AMX0035, a fixed-dose combination of tauroursodeoxycholic acid and sodium phenylbutyrate, is already available in the U.S. under the brand name Relyvrio. It has also gained <a href="https://alsnewstoday.com/news/amx0035-oral-als-therapy-called-albrioza-approved-canada/">conditional approval in Canada</a>, where it is sold as Albrioza — that brand name will also be used in Europe if it&#8217;s approved.
“We share the frustration felt by the European ALS community, who has no time to wait for new, safe, and effective treatment options,” said Stéphanie Hoffmann-Gendebien, general manager and head of Europe, the Middle East, and Africa at Amylyx.
“We remain committed to exploring all potential paths forward in support of the company’s goal of getting AMX0035 to people living with ALS in the EU as quickly as possible,” she added.
The safety and effectiveness of AMX0035 was initially assessed in the CENTAUR trial, which enrolled 137 adults with early and rapidly progressing ALS. Data showed Relyvrio significantly <a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">slowed functional decline</a> and <a href="https://alsnewstoday.com/news-posts/2020/10/19/amylyxs-amx0035-significantly-extends-als-patients-lives-long-term-trial-data-show-also-slows-functional-decline/">extended survival</a>, compared with a placebo.
“AMX0035 is the first and only drug to show an effect on both function and survival in the same trial. Since the medication’s approval with conditions in Canada and full approval in the U.S., thousands of people have been prescribed AMX0035 in North America,&#8221; said Joshua Cohen and Justin Klee, co-CEOs of Amylyx.
[quote=&#8221;center&#8221;]We are disappointed to learn of this outcome, as it is a further setback for the more than 30,000 people living with ALS and their loved ones in Europe who have not seen therapeutic progress for this devastating disease in over 25 years.[/quote]
<h3>Phase 3 PHOENIX trial fully enrolled with 664 participants in US, Europe</h3>
The PHOENIX trial was then launched to confirm the benefits seen in CENTAUR in a larger group of ALS patients. The trial is <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">fully enrolled</a>, with 664 participants recruited across 69 clinical sites in the U.S. and Europe.
Participants were randomly assigned to Relyvrio or a placebo, given daily for 48 weeks, or nearly one year. They will then be given the option to join an open-label extension part, where all will the receive the medication for two years.
The trial&#8217;s main goal is to determine if AMX0035 can slow disease progression, as assessed by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures include changes in lung function and quality of life, and an extension in survival time.
Top-line data are expected by June 2024.
&#8220;ALS has no geographical boundaries, and we are working with urgency toward providing timely, broad, and sustainable access to AMX0035 for eligible people living with ALS who may benefit,” Cohen and Klee added.

CHMP confirms its initial position against approving AMX0035 in EU

The European Medicines Agency (EMA) is now expected to issue a decision in the first months of 2024 on the conditional approval of <a href="https://alsnewstoday.com/masitinib/">masitinib</a> as an add-on oral therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The deadline extension follows a request, seeking more time, from <a href="https://www.ab-science.com/">AB Science</a>, the therapy&#8217;s developer, to the EMA&#8217;s Committee for Medicinal Products for Human Use, known as CHMP. AB Science had asked for additional time to address a recently implemented EMA guideline regarding product manufacturing.
The CHMP is responsible for evaluating available clinical data and issuing a scientific opinion regarding the approval of medicinal products in Europe; delaying the committee&#8217;s opinion will ultimately delay the agency&#8217;s decision on whether to approve the drug.
&#8220;Based on this updated timetable, the CHMP decision on masitinib marketing authorization in ALS is expected during the first quarter of 2024,&#8221; the company stated in a <a href="https://www.globenewswire.com/news-release/2023/09/18/2745073/0/en/AB-Science-provides-an-update-on-the-EMA-timetable-for-examination-of-the-masitinib-marketing-authorization-application-in-ALS.html">press release</a>.
[recommended-reading id=83944]
<h3>AB Science says its manufacturing process complies with new guidance</h3>
The <a href="https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf">new guidance</a>, implemented by the EMA on July 28, is aimed at all applicants with a marketing authorization application for medications with lab-made or biological active substances. It asks all companies to review their manufacturing processes to identify and reduce the risk of nitrosamine impurities, some of which can lead to cancer.
A conventional stop-clock during a drug review — a period of time that allows applicants to respond to questions from the regulatory authority — is usually 30 days. However, the company noted that such an extension would not be sufficient to evaluate its manufacturing process concerning the risk of nitrosamine formation and make any necessary adjustments to meet the guidelines.
Thus, AB Science had requested an extension, which was accepted during this month&#8217;s CHMP session. So far, according to the company, results from its review have not shown any issues that would derail its application.
&#8220;Based on the current stage of investigations, AB Science is confident that the current manufacturing process of masitinib complies with this new EMA guidance,&#8221; the company wrote.
Masitinib is an oral therapy designed to slow disease progression by reducing the activity of certain immune cells that drive inflammation in ALS.
AB Science&#8217;s application requesting the approval of masitinib is based on data from a <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">Phase 2/3 clinical trial (NCT02588677)</a>, called AB10015. That trial evaluated masitinib as an add-on therapy to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> (riluzole), an approved ALS treatment, in 394 patients.
Final results from the trial demonstrated that treatment with a 4.5 mg/kg dose of masitinib for nearly one year <a href="https://alsnewstoday.com/news-posts/2019/07/10/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">significantly slowed disease progression</a> — by 27% — in people with a so-called normal disease progression. Specifically, that means a monthly decline in the ALS Functional Rating Scale-Revised scores of less than 1.1 points.
This higher dose also resulted in slower declines in lung function and quality of life.
While no significant survival differences were observed in the overall population, a significant survival benefit was detected when only people with mild or moderate disease were included in the analysis. In that group, masitinib-treated patients lived more than two years longer than those on Rilutek alone, representing a 44% reduction in the risk of death.
Conditional approval in the EU is granted to medicines that immediately fulfill an unmet medical need — for therapies whose preliminary benefits outweigh their potential risks. If granted, masitinib will be marketed in Europe under the brand name Alsitek.
Still, because a full approval will require confirmatory clinical trials, AB Science already is conducting a global <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a>, called AB19001, to confirm the benefits of adding masitinib to Rilutek.
In that study, about 495 participants will be randomly assigned to take one of two daily doses of masitinib (4.5 or 6 mg/kg), or a placebo, for 48 weeks, or nearly one year. The trial’s main goal is to determine the effect of treatment on disease progression, but its impact on quality of life, lung function, muscle strength, and survival also will be assessed.

Tag: European approval process

OrphAI’s AIT-101 granted orphan drug status in Europe for ALS

Committee favors EU approval of Qalsody for adults with SOD1-ALS

CHMP confirms its initial position against approving AMX0035 in EU

Early 2024 eyed for approval decision in EU on masitinib for ALS