BVS857 Clinical Trial Yields Mixed Results

Below is another article reporting the results of the BVS857 Trial. Click on the link to read the article at SMA News Today.

 

BVS857 Clinical Trial Yields Mixed Results

BY ALICE MELÃO

Novartis Pharmaceuticals‘ investigational compound BVS857 significantly improved muscle volume in patients with X-linked type spinal muscular atrophy (SMA) over a short period of time, Phase 2 clinical results show. However, the compound failed to improve muscle strength and function.

These findings were reported in the study, “Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial,” published in The Lancet Neurology.

X-linked type SMA, also known as spinal and bulbar muscular atrophy (SBMD), or Kennedy’s disease, is caused by a faulty androgen receptor (AR) gene and is characterized by degeneration of muscle and lower motor neurons of the brain stem and spinal cord.

Previous studies have shown that patients with this disease have low amounts (less than 170 ng/mL) of insulin-like growth factor-1 (IGF-1) in the blood. Also, cellular and mouse studies have suggested that by increasing the amount of this signaling molecule it may be possible to ease the features of AR gene mutations.

IGF-1 is a growth factor with different roles in many aspects of childhood growth. It also plays an important role in adult metabolism.

Novartis developed the artificial compound BVS857 specifically to mimic the natural activity of the IGF-1 hormone, while holding enhanced efficiency. This molecule is capable of IGF-1 receptor activation, but has a longer half-life — the time it takes for the body to eliminate half of the substance — than IGF-1.

The safety and effectiveness of BVS857 was evaluated in a Phase 2 trial (NCT02024932) in adult patients with genetically confirmed Kennedy’s disease recruited at six clinical sites in Denmark, Germany, Italy, and the United States. Patients were at least 18 years old, were ambulatory, had muscle weakness and IGF-1 blood serum levels below 170 ng/mL.

The study was divided into two parts. The first part included eight patients who received increasing doses of the investigational compound or a placebo. In the second part, 27 patients received weekly intravenous injections of 0.06 mg/kg BVS857 or placebo for up to 12 weeks.

During the study 89% and 94% of the patients in the placebo and BVS857 groups, respectively, experienced at least one adverse side effect, with the proportion of moderate adverse side effects being higher in the BVS857-treated group.

The most common treatment-related side effects were inflammation of the nose and pharynx, and headache. In general the treatment was found to be safe without inducing any serious problems.

Repeated treatment with BVS857 induced a significant increase in IGF-1 levels up to a mean value of 788 ng/mL.

Evaluation by magnetic resonance imaging (MRI) scans revealed that BVS857 could induce a significant, but mild, improvement of thigh muscle volume (TMV) — a marker of muscle wasting — compared to initial values. Also, TMV in BVS857-treated patients remained stable during the trial, while it decreased in the placebo group.

However, new assessment of TMV approximately 21 and 48 days after completion of the treatment showed no significant differences between the two groups.

BVS857 also failed to induce significant improvements on disease symptoms, as determined by the Adult Myopathy Assessment Tool score, and lean body mass when compared to placebo after 12 weeks.

“Overall, no significant differences were found in any of the motor functional measures between the BVS857 and placebo groups,” researchers wrote.

During the trial, about 72% of the patients on the BVS857 treatment group developed antibodies against both the investigational compound and natural IGF-1, which in 46% of the cases had a neutralizing effect. This enhanced immunoreactivity was fully resolved upon treatment discontinuation.

Collectively, these results demonstrated that IGF-1 pathway activation over a short period of time can significantly improve muscle volume in patients with Kennedy’s disease. Still, it failed to improve muscle strength and function.

“The evidence of preliminary efficacy over the short timeframe of 12 weeks in this study is encouraging and not previously described,” researchers wrote. “Activation of the IGF-1 pathway by other means, perhaps in combination with an anti-androgen drug, might be worth pursuing in future clinical trials.”

“We believe this result has implications for other clinical proof-of-concept studies in patients with muscle atrophy or wasting,” researchers concluded.

Trial Shows Positive Initial Results for IGF-1

This is a follow-up article written by Lucy Piper on the IGF-1 trials that is written more for the layperson. It was published in Medwire News. Click on the link below to read the article at Medwire.

Positive initial results for IGF-1 pathway as treatment target in spinal and bulbar muscular atrophy

medwireNews: The insulin-like growth factor-1 (IGF-1) pathway may be a suitable treatment target for patients with spinal and bulbar muscular atrophy, suggest preliminary findings.

“By targeting the IGF-1 pathway in spinal and bulbar muscular atrophy, we aimed to replenish the reduced IGF-1 concentrations found in this disease, to stimulate downstream Akt activity to reduce the toxicity of the mutant androgen receptors, and to increase anabolic activity to prevent muscle loss”, the researchers explain.

They examined the tolerability and preliminary efficacy of the IGF-1 mimetic BVS857 in 27 patients, of whom 18 who were randomly assigned to receive the drug while nine were assigned to placebo.

The patients, aged at least 18 years, were ambulatory, had symptomatic weakness and had serum IGF-1 levels of 170 ng/mL or below.

The patients given BVS857 0.06 mg/kg intravenously once a week for 12 weeks showed a significant improvement from baseline in thigh muscle volume – a marker of muscle wasting and denervation – on magnetic resonance imaging scans, compared with placebo, with a geometric mean ratio of 1.04 in favour of the treatment.

Specifically, thigh muscle volume remained stable in the patients taking BVS857, whereas it declined in the placebo group over the course of treatment.

Improvements in the Adult Myopathy Assessment Tool score were seen in both groups, at 7.0% in the placebo group and 4.9% in those taking BVS857, but there was no significant difference between the two. There was also no change in lean body mass in either group.

There was a similar positive change in EQ-5D score for the two groups and a significant improvement with BVS857 over placebo in SF-36 Mental Component Score.

The researchers, led by Christopher Grunseich (National Institutes of Health, Bethesda, Maryland, USA), note in The Lancet Neurology that there was no treatment effect on muscle function, which may be “a consequence of the small effect on muscle volume.” And there was no increase in Akt signalling in monocytes or muscle biopsy samples possibly as a consequence of “the short duration of the increase in total IGF-1 equivalency”, they propose.

In a related commentary, Atsushi Hashizume and Masahisa Katsuno, both from Nagoya University Graduate School of Medicine in Japan, say that the discrepancy between a positive drug effect on thigh muscle volume and clinical outcomes “suggests a need for identification of novel biomarkers that reflect both biological and clinical effects of IGF-1 mimetics and related drugs.”

They add that “extension of the half-life of IGF-1 is key to improving the biological effects of this therapy in patients with spinal and bulbar muscular atrophy.”

BVS857 was otherwise generally well tolerated, with no cases of hypoglycaemia, Bell’s palsy or serious adverse events. However, immunogenicity was detected in 72% of patients taking BVS857, which “limits its use as a therapeutic drug”, note Grunseich and team.

They conclude that the findings are “encouraging” and call for further trials with sufficient power and longer duration to better assess the effects of IGF-1 targeting on muscle strength and function.

“Activation of the IGF-1 pathway by other means, perhaps in combination with anti-androgen drug[s], might be worth pursuing in future trials,” they suggest.

By Lucy Piper

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

Image:  https://www.alpco.com/role-igf-1-growth-hormoneigf-axis

IGF-1 Clinical Trial for Kennedy's Disease

The Lancet – Neurology published the following article yesterday on the IGF-1 clinical trial for Kennedy’s Disease (SBMA). Below are excerpts of the Summary. The full Summary can be read at the link below and the article can also be purchased on the website.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Summary

Background

“Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. …”

Methods

“In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). …”

Findings

“31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. …”

Interpretation

“TMV (thigh muscle volume) remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. …”

Note:  There is an accompanying article also noted:

IGF-1for spinal and bulbar muscular atrophy: hope and challenges

Image:  http://www.hgh-pro.com/igf-1.html

Kennedy’s Disease BVS857 Trial

Many of us have been patiently awaiting the published report on the recently concluded Kennedy’s Disease BVS857 trial at NIH. Two of the attendees provided the following information on the trial. Once the actual paper is published, I’ll provide a link to it

.

Dr. Kenneth Fischbeck of the NIH gave a report on this trial at the KDA Conference in San Diego last week. He stated that while there were some modest positive results it did not meet expectations. In part that may have been because they only conducted the trial for 12 weeks and the nature of the drug and its effect would suggest slowly increasing benefits over an extended time frame.

The compound was intended to improve insulin sensitivity in people with KD and boost the anabolic effects of insulin and IGF1. Unfortunately, it also stimulated an immune response in some patients taking it producing anti-bodies that not only attacked the drug but also attacked the person's own insulin or IGF1. Fortunately for those affected after discontinuing the drug the immune response faded. Novartis aborted their trial plans and terminated further investigation of the compound.

The following is a quote from Dr. Fischbeck. “We too are disappointed that the Novartis agent was not more effective, but we are optimistic that the results from this trial will help in developing a treatment that really works for Kennedy’s disease. The study gave us information about muscle imaging and clinical outcome measures that will improve the design of future trials, and it helped to set up a network of trial sites that will allow clinical studies to be done more efficiently. Also, it gave an indication in the effect on muscle size that other drugs targeting the same pathway might be effective.”

The BVS857 Trial is Completed

Most of us living with Kennedy's Disease are anxiously awaiting news of the BVS857 trial. If you can't remember what the trial is, follow this link:  Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy

I also wrote about it in earlier blogs:

• Information on the NIH Clinical Trial
• Update on Clinical Trial  - Link to Video

 Yesterday I reached out to Dr. Fischbeck at NIH. He was kind enough to respond to my inquiry. I realize it isn't anything definitive, but it means the results will be published soon.  FINGERS CROSSED

Thanks for the message, Bruce. The active phase of the BVS857 trial has ended, and the results are being analyzed. We currently plan to present the findings at the KDA meeting in the fall, and will likely be able to get some word out earlier, hopefully in the next month or two.

It’s OK to let the others know.

Kurt

Update on the Novartis Drug BVS857 Clinical Trial

I asked Dr. Fischbeck for an update on the current clinical trial at the NIH. He provided the following:

Our current trial of Novartis drug BVS857 here at the NIH now includes 8 sites, 4 in the US and 4 in Europe. Information about it can be found at the ClinicalTrials.gov website: https://clinicaltrials.gov/ct2/show/NCT02024932. The trial is progressing well, and with the added sites we hope to finish it in a few months. We won’t know the results until the trial ends and the data have been analyzed, but at this point I am optimistic.

If the current trial shows a robust benefit, then a follow-on study to confirm safety and efficacy is likely, and that could well include additional sites. Meanwhile we are in discussions with other companies about new drugs to try, perhaps by late 2016 or early 2017.

When Dr. Fischbeck uses the words, '... at this point I am optimistic', it brings a smile to my face and a flash of hope. With eight sites involved in the trial, the results should be more indicative of what we can expect if, and I use the word IF, BVS857 should ever become available. 

The clock is ticking for some of us living with Kennedy's Disease (SBMA), but that doesn't mean that many of us, including future generations, won't reap the benefits of a treatment for this condition. So, stay tuned and don't give up hope.

Update on BVS857 Clinical Trial

Below is a link to a short video update given by Dr. Fischbeck of the National Institutes of Health on Phase 2 of the clinical trial using a Novartis drug called BVS857. The trial is being held in several locations in the United States and Europe. Dr. Fischbeck uses the terms 'encouraging' and 'promising' in his comments on this study.

That is encouraging for me. :-)

"In this exclusive interview, Kenneth Fischbeck, MD, of the National Institute of Neurological Disorders and Stroke (NINDS) talks about the recent studies being conducted at the NINDS, in collaboration with Novartis, to understand, and find a treatment for, Kennedy's disease (spinal and bulbar muscular atrophy)."

http://www.raredr.com/videos/Kennedys-Disease

For more about this trial, follow this link: https://clinicaltrials.gov/ct2/show/NCT02024932