VHB937 for ALS

(ASTRALS Trial)

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must not be taking: Prohibited medications

Disqualifiers: Cardiac conditions, Liver disease, Psychiatric disease, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 10

Duration: 40 weeks

225 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that you should not be taking any prohibited medications. If you are on a stable dose of an approved ALS treatment, you may continue with it.

What data supports the effectiveness of the drug VHB937 for ALS?

The CENTAUR trial showed that a combination of sodium phenylbutyrate and taurursodiol, similar to VHB937, was safe and effective for ALS, leading to its approval in Canada and the USA. ^{1 2 3 4 5}

How does the drug VHB937 differ from other ALS treatments?

VHB937 is unique because it involves the overexpression of the VAPB protein, which may help protect motor neurons and slow disease progression in ALS. This approach targets a specific genetic pathway, potentially offering a new angle compared to existing treatments that do not focus on VAPB. ^{6 7 8 9 10}

What is the purpose of this trial?

This is a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase II study to evaluate the efficacy and safety of VHB937 in participants with early-stage ALS (within 2 years of ALS symptoms onset). The study comprises a core double-blind (DB) 40-week treatment period followed by an open label extension (OLE).

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for adults over 18 with early-stage ALS, diagnosed within the last two years and having mild symptoms. Participants must not have started any ALS treatment or be on a stable approved dose. They should also have a certain level of breathing function and agree to use strict contraception if they can have children.

Inclusion Criteria

My ALS diagnosis has been confirmed by the trial's doctors.

I am using effective birth control.

My ALS symptoms are mild, with an ALSFRS-R score of 30 or more.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive VHB937 or placebo via I.V. infusions every 4 weeks during the double-blind period

40 weeks

10 visits (in-person)

Open-label extension

Participants may continue to receive VHB937 in an open-label extension phase

60 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• VHB937

Trial Overview The study tests VHB937 against a placebo in people with early-stage ALS. It's randomized (participants are put into groups by chance), double-blind (neither doctors nor participants know who gets what), and includes an initial 40-week treatment period followed by an open label phase where everyone knows what they're getting.

Participant Groups

Group I: Arm 1 Experimental Treatment 1 Intervention

I.V. infusions

Group II: Arm 2 Placebo Group 1 Intervention

I.V. infusions

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Sodium phenylbutyrate-taurursodiol (PB-TURSO) has been shown to be safe and effective for treating amyotrophic lateral sclerosis (ALS), leading to its conditional approval in Canada and full approval in the USA after the CENTAUR trial, which was a randomized, double-blind, multicenter study.

The ongoing phase 3 PHOENIX trial will further evaluate the safety and efficacy of AMX0035, a combination of PB and TURSO, but its high annual cost of $158,000 may limit access for patients with ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. Sun, Y., Li, X., Bedlack, R.[2023]

Currently, the only FDA-approved drugs for ALS are riluzole, which modestly slows disease progression, and edaravone, which has also been shown to slow progression, offering some hope for patients.

Multidisciplinary clinics and symptomatic treatments play a crucial role in improving the quality of life for ALS patients and can help prolong their lives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Introduction to supplement: the current status of treatment for ALS. Miller, RG., Appel, SH.[2018]

A new self-reported ALS disability scale called the Rasch-Built Overall ALS Disability Scale (ROADS) was developed, consisting of 28 questions that showed improved item targeting and high test-retest reliability (0.97) compared to the existing ALS Functional Rating Scale (ALSFRS-R).

The ROADS scale demonstrated better psychometric properties and responsiveness, making it a potentially valuable tool for assessing disability in ALS patients during clinical trials and in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and Validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). Fournier, CN., Bedlack, R., Quinn, C., et al.[2021]

Over the past 20 years, the mean age of onset for amyotrophic lateral sclerosis (ALS) has increased, with a notable rise in cases among patients over 70 years old, indicating a demographic shift in the disease's presentation.

Patients with combined type ALS experience a significantly shorter time to primary end-point (PEP) compared to other types, suggesting that the progression rate of symptoms is a critical prognostic indicator for survival in ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The changes of clinical characteristics in 100 Japanese amyotrophic lateral sclerosis patients between 1980 and 2000]. Kimura, F., Shinoda, K., Fujiwara, S., et al.[2006]

In a study of 221 ALS patients, the rate of symptom progression, particularly in respiratory and bulbar functions, was found to be a significant predictor of disease outcome, highlighting the importance of early monitoring.

Factors such as age at onset, the classification of ALS severity, and treatments like riluzole and percutaneous endoscopic gastrostomy also played crucial roles in determining patient survival, with median survival times of 915 days from symptom onset and 580 days from diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early symptom progression rate is related to ALS outcome: a prospective population-based study. Chiò, A., Mora, G., Leone, M., et al.[2019]

In a study of 755 sporadic ALS patients and 111 familial ALS patients, researchers identified a novel mutation (p.V234I) in the VAPB gene in a familial ALS patient, suggesting a potential genetic link to the disease.

The p.V234I mutation was not found in control subjects, indicating its rarity and possible significance in ALS, further supporting the idea that multiple genetic factors may contribute to the development of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. van Blitterswijk, M., van Es, MA., Koppers, M., et al.[2017]

Overexpressing wild-type human VAPB in a mouse model of familial ALS significantly slowed neurological decline and prolonged survival of spinal motor neurons, suggesting a protective role for VAPB in motor neuron health.

The study indicates that enhancing VAPB levels may counteract some effects of ALS, as evidenced by improved muscle denervation and a slight extension in lifespan in the SOD1 G93A transgenic mice model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS. Kim, JY., Jang, A., Reddy, R., et al.[2018]

In a study analyzing the presence of VAPB protein fragments in the cerebrospinal fluid (CSF) and peripheral blood leukocytes (PBL) of patients with sporadic ALS (SALS), it was found that a significant number of bulbar-onset SALS patients (58.7%) lacked the 14 kDa VAPB MSP fragment in their CSF, indicating a potential alteration in VAPB processing in this subgroup.

The findings suggest that the absence of the VAPB MSP fragment may be linked to the pathophysiology of bulbar-onset SALS, highlighting the importance of VAPB in motor neuron diseases and warranting further investigation into its role as a potential biomarker or therapeutic target.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of vesicle-associated membrane-protein-associated protein B cleavage products in peripheral blood leukocytes and cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Deidda, I., Galizzi, G., Passantino, R., et al.[2015]

Genetic research has identified numerous mutations linked to amyotrophic lateral sclerosis (ALS), which can help explain the disease's varied clinical presentations and improve clinical trial outcomes.

Advanced genetic sequencing techniques are paving the way for better patient stratification in clinical trials, allowing for more personalized treatment approaches and improved understanding of ALS's underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. Su, XW., Broach, JR., Connor, JR., et al.[2015]

A study involving 973 Swedish, 126 Portuguese, and 19 Icelandic ALS patients found that mutations in the VAPB gene, including a novel missense mutation, were present in both ALS patients and healthy controls, suggesting these mutations are not directly linked to the disease.

The presence of VAPB mutations in healthy relatives and the lack of clinical differences in patients with these mutations indicate that they are unlikely to be pathogenic, challenging the assumption that VAPB mutations contribute to ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland. Ingre, C., Pinto, S., Birve, A., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Introduction to supplement: the current status of treatment for ALS. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Development and Validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

[The changes of clinical characteristics in 100 Japanese amyotrophic lateral sclerosis patients between 1980 and 2000]. [2006]

5. United States pubmed.ncbi.nlm.nih.gov

Early symptom progression rate is related to ALS outcome: a prospective population-based study. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Expression of vesicle-associated membrane-protein-associated protein B cleavage products in peripheral blood leukocytes and cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. [2015]

10. England pubmed.ncbi.nlm.nih.gov

No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland. [2015]