Tag Archives: 21st Century

Radicava Approved By FDA

Radicava Approved By FDA!

May is ALS awareness month and we are pleased to announce genuine progress in modernizing the clinical trial process and in fighting this disease. On May 1, 2017 Hope NOW for ALS facilitated a meeting with key officials at the FDA and was joined by the ALS Association. Devising smarter clinical trial designs (“21st Century Clinical Trials”) will speed up the pace of discovery and lead to faster approval of viable treatments, while also funneling resources to the most promising therapeutics. The involvement of the ALS patient community is largely responsible for this progress which represents a seismic shift in trials for ALS. We will continue to collaborate with others in the ALS community to accelerate the process of finding additional treatments and a cure.

On May 5, 2017 the FDA approved edaravone (brand name Radicava) for the treatment of ALS. Developed by MT Pharma America, this drug was approved in Japan in 2001, originally to protect against the effects following ischemic stroke, and approved there for ALS in 2015. The FDA actively engaged with the sponsor and approved the treatment without requiring additional trials to be conducted in the US. We believe the FDA acted with the flexibility granted to them by Congress by accepting data from trials conducted outside the U.S. without not sacrificing the statistical rigor needed to show efficacy of the treatment. While Radicava is not a cure, it has been shown to significantly slow progression in some patients (up to 33% slower progression in PALS <2 years post-diagnosis). We believe it represents an important new treatment option for ALS patients and demonstrates to other medical sponsors and investors that effective treatments can be developed - and expediently approved - to fight ALS.

Hope NOW for ALS is committed to active engagement with the FDA, the ALS Association, and other ALS organizations to promote clinical trial designs tailored to the nature of this disease. The past few decades have demonstrated that standard trial designs have been ineffective in providing clear answers on the effectiveness of potential treatments for ALS. Inefficient trial designs make it hard to identify effective treatments and can lead to wasted investments in treatments that do not work. The FDA acknowledges the difficulties in designing trials utilizing homogeneous treatment and placebo arms for a highly variable disease like ALS, and has indicated receptivity to newer, customized trial designs. ALS has significant variations and lacks a predictable course. Some of the ideas now circulating regarding ALS-specific trial designs include incorporating historical controls, predictive algorithms, and leveraging individuals existing progression data. In addition, more information can be gleaned from trial data by controlling for severe adverse events (SAEs) unrelated to the treatment. In instances where researchers feel that a placebo arm is necessary, crossover designs can be utilized to increase patient access to the treatment, and enhance the power of the data.

We have good reason to believe that significant progress is, and will, continue to occur. Together, with the sustained involvement of the patient community, we will accelerate the pace of finding a cure.

Facebooktwittergoogle_plusredditpinterestlinkedinmail

HNFA Progress Update – 12-08-2016

Predictive Algorithms To Revolutionize Clinical Trials

EXCITING NEWS! Hope NOW for ALS has been busy this year meeting with the FDA, researchers, and bio/pharma companies to promote a methodology for faster, less expensive, more accurate, and more humane trials. Specifically, we have been advocating the use of predictive algorithms that can reduce or eliminate the need for a placebo arm, and reduce the number of patients necessary to achieve the FDA’s required measure of statistical significance (p < 0.05). This will result in faster delivery of promising treatments.

This week Origent Data Sciences and Cytokinetics announced their collaboration for the Phase 3 trial of Tirasemtiv (VITALITY-ALS). Hope NOW for ALS played an important role in brokering this partnership and encouraging the ALS Association to provide grant funding. This collaboration represents a vital step forward in how ALS clinical trials are conducted and hastens efforts to find effective treatments. Thank you for your continued support!

Read the announcement here: https://globenewswire.com/news-release/2016/12/07/895765/0/en/Origent-Data-Sciences-and-Cytokinetics-Present-Analyses-Demonstrating-Baseline-Data-Predict-Measures-of-Vital-Capacity-in-Patients-With-ALS.html

Facebooktwittergoogle_plusredditpinterestlinkedinmail

The Significance Of The Sarepta Approval

THE SIGNIFICANCE OF THE SAREPTA APPROVAL

The FDA’s granting of Accelerated Approval (AAP) for Sarepta’s eteplirsen for Duchenne Muscular Dystrophy (DMD) marks a clear turning point in thinking at the FDA. DMD, not unlike ALS, poses very real challenges to the traditional clinical trial process. With a small disease population (13% of an already-small DMD population who have the particular genetic abnormality the drug targets) consisting of young boys, the option of a large Phase 3 randomized double blind placebo concurrent control trial that can produce a p-value of less than 0.05 (the chance of the result being random and not connected to the drug) is untenable from both a practical and financial point of view. That being said, reliance on the old norm doesn’t even begin to address the ethical concerns of giving young boys placebos in the face of a crippling and fatal disease.

In this case, the manufacturer opted for a very small single arm trial and utilized two European studies of DMD natural history as a control. The trial participants’ feedback proclaimed efficacy. Traditionalists roared back “placebo effect”. Patient and parent advocacy groups as well as Right To Try proponents screamed foul and the battle lines were drawn.

Last spring the FDA conducted a long-awaited hearing of an advisory panel which, on a close vote, declined to find “efficacy” and recommended against AAP. What happened next was quite remarkable and indeed a rare instance of the exercise of forward-thinking judgment on the part of government officials, principally Dr. Robert Califf (the FDA commissioner) and Dr. Janet Woodcock (head of the FDA’s Center for Drug Review). They utilized the flexibility afforded them by Congress many years ago to grant Accelerated Approval to the drug, subject to a Phase 4 confirmatory trial. In other words the patients could get access to the medication, the manufacturer could recover its investment and make a profit, and the FDA could continue to assess efficacy and control access to the drug. That might just be what Congress intended – a novel possibility.

While AAP is not uncommon in the areas of oncology and HIV, this represents the first use of AAP in the case of a neurodegenerative disease. Everyone wins except the long-time FDA staff members who still complain, calling eteplirsen an “elegant placebo”. Perhaps it is time for them to move on and for patients to stop dying in slow and very non-elegant clinical trials.

What does this mean for ALS? In four short letters “HOPE”. We strongly believe ALS patients and drug and biologic manufacturers are in a much better position to take advantage of this path and the FDA’s openness to use it, something HopeNowForALS has been championing for the past several years. Some points to consider are:

  • The heterogeneity of ALS and the non-linear progression patterns of most patients present similar but different problems to DMD, but they also make the current randomized double-blind placebo-control trial more likely to produce Type 1 (false positive) or Type 2 (false negative) errors than produce an accurate assessment of the treatment;
  • In many ALS trials, blood, cerebrospinal fluid, and other tests can conclusively show biologic effect in patients (eg reductions in markers of inflammation, etc.) just like dystrophin levels did in DMD patients. When those effects are shown there is even more reason to consider alternatives to concurrent placebo controls;
  • With the records of thousands of placebo patients from ALS trials housed in the ProAct database, we are in a much better position to construct highly statistically powered homogeneous controls than even the DMD investigators were. This way it is possible to create a highly-powered matched control on a patient-by-patient basis for those in the treatment arm, thereby establishing expected mean progression with accuracy previously thought impossible. Predictive progression algorithms offer yet another alternative to the traditional concurrent placebo control;
  • While not a perfect solution, these advances, along with better ideas on patient stratification within trials, will prove extremely meaningful in reducing statistical noise. With that noise reduction, both Type 1 and Type 2 errors are dramatically reduced in ALS trials. In short, they are a better and smarter alternative to the status quo. It just takes courage and intelligence to recognize these things, like that exhibited by Drs. Califf and Wooodcock.

Treatments in development like tirasemtive, NurOwn, NP001, Radicut, and others on the horizon can utilize these 21st century innovations to present their case for AAP in a strong and intelligent way to the FDA, without either bankrupting themselves or delaying the process for years at time while they seek investments from the capital markets to conduct still-flawed and expensive Phase 3 trials. Even more innovative trial designs have now become possible, utilizing more robust run-in data on trial participants who participate in Precision Medicine Programs like the ALS-TDI program. It’s now time for “big data” to meet “big science” at the intersection of ALS and take advantage of this extraordinary opportunity the FDA has put within our reach.

We applaud Dr. Califf and Dr. Woodcock for recognizing there is more than one way to construct an adequate trial control group, and promise to keep working with them. We pledge our every effort in pushing HopeNowForALS to take its place as an agent for change in clinical trial design for this deadly and monstrous disease.

Robert Hebron
Chairman
Hope NOW for ALS

Board of Directors:

Bob Hebron (ALS caregiver, NJ)
Jehad Majed (ALS caregiver, MI)
Linda Clark (widowed ALS caregiver, CA)
Eric Valor (person with ALS, CA)
Dr. Stephen Finger (person with ALS, SC)
Jay Smith (person with ALS, TX)

Email: info@hopenowforals

Facebooktwittergoogle_plusredditpinterestlinkedinmail

BRAINSTORM PHASE 2 RESULTS

BRAINSTORM CELL THERAPEUTICS PHASE II TRIAL RESULTS

July 18, 2016

Hope NOW For ALS is honored to be participating with Brainstorm and its statisticians and investigators in the analysis of their U.S. phase 2A clinical trial of NurOwn. Today Brainstorm announced the results of that trial. First, and most importantly, the trial demonstrated safety beyond any doubt. The trial was a randomized double-blind placebo group trial conducted at three centers: Massachusetts General Hospital, University of Massachusetts Medical Center and the Mayo Clinic. Two-thirds of the patients received the treatment and one-third a placebo. Initially 48 patients were enrolled; three dropped out at mid-trial. While the trial was not sufficiently powered to attain the FDA’s traditional definition of efficacy (a P value < 0.05 comparing mean progression of the treated group to the placebo group), an in-depth analysis of the data indicates significant and positive results.

First, looking at the “responders” (ALSFRS score progression rate pre-treatment (3 months) is slowed by 100% or more after treatment), there was a clear, disproportionate favorable impact in the treatment group at 2 and 4 weeks. A few positive responses in the placebo group indicate the presence of a “placebo effect” (when patients receiving a placebo feel they are improving). However, by week 12 the placebo effect all but disappeared. The responders (40% of the treated group) however, still showed positive responses at week 12. The degree of positive response was noticeably diminished by week 24. Significantly, if a “responder” is defined as one whose ALSFRS score slope improves by 1.5 points per month, at 4 weeks post treatment nearly half of the treated group met the definition of “responder”, and only one in the placebo group. At 12 weeks, approximately 25% of the treated group still met the definition of “responder” and no one in the placebo group. Clearly the treatment produced a beneficial impact for a significant percentage of the trial participants.

When slow progressors are excluded from the data analysis, benefits are easier to detect and the results appear even more favorable. (Unfortunately, the power of this subset analysis is probably insufficient to persuade the FDA to grant approval). In addition, as Dr. Merit Cudkowicz observed, after 2 weeks the treated group showed increased levels of growth factors and decreased inflammatory markers in their cerebrospinal fluid (”CSF”) – strong evidence of a biological effect. When coupled with the responder analysis, it underscores the positive results.

The timing of the observed improvements was relatively consistent with the science concerning stem cell therapy; repeated applications are suggested to be most effective due to the relatively short half-life of stem cells once introduced into the body.

Hope NOW For ALS performed an additional analysis looking at demographic patterns in the trial population as possible predictors of responses. We found a relatively high correlation in responders to: 1) age, and 2) baseline SVC level. The majority of the responders were under age 51 with an SVC ≥ 80% at the start of the trial. Responders older than 51 all had an SVC ≥100% at the start of the trial. This observation produces the algorithm below to predict responders and non-responders:

Likely responders: Age of patient ÷ (0.1 × SVC) < 7.0

Brainstorm and clinical trial investigators have indicated a desire to conduct a higher powered Phase 3 trial. While we support this, we also know that raising the necessary funding from investors for a Phase 3 trial could be a very lengthy process, possibly years. Hope NOW For ALS believes the evidence of efficacy in the Phase 2 trial warrants applying for an Accelerated Approval (AAP), subject to a Phase 4 confirmatory trial. Discussions with the FDA should begin immediately. We are eager to assist Brainstorm and the investigators to bring this extremely promising treatment to the clinic as soon as possible. We join Brainstorm in thanking the patients who participated in this trial – you are making a significant contribution to the pursuit of a cure.

Hope NOW for ALS

Board of Directors:

Bob Hebron (ALS caregiver, NJ)
Jehad Majed (ALS caregiver, MI)
Linda Clark (widowed ALS caregiver, CA)
Eric Valor (person with ALS, CA)
Dr. Stephen Finger (person with ALS, SC)
Jay Smith (person with ALS, TX)

Email: info@hopenowforals.com

Facebooktwittergoogle_plusredditpinterestlinkedinmail