On June 14, 2022, ICER released its draft evidence report, “AMX0035 and Oral Edaravone for Amyotrophic Lateral Sclerosis.” This is the first step in ICER’s review process. A final evidence report is expected to be released in mid-September.
Background on ALS
Amyotrophic Lateral Sclerosis (ALS) is a devastating, rapidly progressing disease of central nervous system degeneration. Symptoms of ALS include physical or bodily weakness, cognitive decline, and uncontrolled and variable emotional responses. Because ALS has no specific symptoms or diagnostic test, it often takes a year or longer for people with ALS to be correctly diagnosed. Life expectancy after the onset of symptoms is typically three to five years, which means two to four years after diagnosis. Death from ALS usually occurs due to respiratory failure, or from pneumonia resulting from weakness in the respiratory muscles.
The cause of ALS is unknown, but it is believed to result from a combination of age and environmental and genetic factors. About 10% of cases of ALS seem to be related to a family history of the disease, and it occurs more often in older people.
Because ALS is such a rapidly progressing disease, early diagnosis is critical, but very challenging. Current treatments focus primarily on supportive care, which requires a multi-disciplinary approach. Specialized ALS treatment centers have been created across the United States. However, because people with ALS have difficulty with movement, and become increasingly dependent on caregivers as their illness progresses, physically accessing those specialized centers can be difficult, particularly for people who live far from them or have limited resources to support their transportation and care needs.
Federal law has been changed on at least two occasions to enable people with ALS to access federal benefits more quickly.
- Since the early 1970s, federal law has stipulated that Social Security Disability Insurance (SSDI) beneficiaries who have not yet reached age 65 (the age when Medicare benefits typically start) become eligible for Medicare after receiving 24 months of SSDI benefits. In 2001, the law was changed so people with ALS who receive SSDI benefits no longer have to endure a 24-month waiting period for Medicare, and instead became eligible at the same time they start receiving SSDI benefits.
- Since its inception in the 1950s, the SSDI program has required beneficiaries to wait to receive benefits for five months from the date the beneficiary’s disability began. Many patients with ALS deteriorate rapidly or even die during those five months. In 2020, the law was changed to eliminate the five-month waiting period for SSDI benefits for people with ALS.
Existing & Emerging Treatments
ICER’s draft report states, “There is tremendous need for new therapies for ALS, a disease that rapidly leads to severe disability and death in many patients.” However, because the specific cause and underlying disease process for the neurological degeneration in ALS is unknown, developing treatments has been challenging from a scientific perspective.
An additional logistical challenge for clinical research involving people with ALS is related to how quickly patients with ALS can receive treatment. Starting use of an experimental treatment as early as possible – before significant neurological damage has occurred – is preferred because it means that the effectiveness is likely to be greater. However, because ALS diagnosis is often delayed until the illness has advanced, it can be extremely difficult to enroll patients in the earliest stages of the disease in clinical trials.
Existing treatments for ALS include riluzole, a drug that is administered orally, and edaravone, a drug that was approved in 2017 for intravenous administration. Both have been shown to slow ALS progression to some degree.
The current ICER review focuses on two emerging ALS treatment options. The first is AMX0035, a combination of two compounds that is taken orally. Its application is pending before the FDA, and additional clinical trials are ongoing. The second is an oral form of edaravone, which was approved by the FDA on May 12, 2022.
Each of these three treatment options – riluzole, AMX0035, and oral/IV edaravone – is believed to work via a different physiological or pharmacological mechanism of action:
- Riluzole blocks transmission of glutamic acid, which is a neurotransmitter in the Central Nervous System. This action is thought to protect neurons from degrading under toxic stress that is thought to occur with ALS, or because too much glutamic acid itself causes injury to nerve cells.
- Edaravone is a free radical scavenger. Free radicals are molecules that are thought to cause injuries to nerves and other cells.
- AMX0035 is a combination of two compounds. One, sodium phenylbutyrate, reduces stress on the “endoplasmic reticulum,” which is the part of cells where proteins are produced. The other, taurursodiol or Tauroursodeoxycholic acid, reduces mitochondrial dysfunction and possibly other cellular protective effects. Mitochondria are the parts of cells that produce energy for the cells to operate; without mitochondria, cells cannot function properly or repair themselves.
ICER noted the importance of these differences, stating that “effective therapy of ALS is likely to require targeting multiple pathways.”
In its report, ICER evaluated AMX0035 and oral edaravone completely separately because “each drug was studied in different populations and the interventions were not compared to each other.” The report reviews AMX0035 as an addition to the “standard of care,” defined as multidisciplinary care, ± riluzole, ± intravenous edaravone, vs. the standard of care alone. It reviews oral edaravone as an addition to the “standard of care,” defined as multidisciplinary care ± riluzole, vs. the standard of care alone.
Once again, AMX0035 is undergoing FDA review, with a decision expected by September 29, 2022. The application was based upon a phase 2 trial, along with data from a continuation trial of people in the original phase 2 trial, i.e., both people who received AMX0035 and placebo were then able to take AMX0035 after the trial ended. The results from the phase 2 trial and its extension were encouraging, but not overwhelming. Basically, the combination of the original phase 2 trial and its continuation showed slower progression and increased survival of several months (see Fig. 2), and delays in requiring a tracheostomy for ventilation support or needing hospitalization.
However, the sponsor company and its academic researchers view the specific magnitude of those benefits differently than the FDA views them. The data is complicated, and the different analytical and statistical methods that were used to evaluate the data produced somewhat different conclusions. ICER notes those complexities in its draft evidence report, but concludes that AMX005 “demonstrated modest benefits in slowing ALS progression during the randomized phase, as measured by the ALSFRS-R score, and a 5-month survival benefit with longer-term follow-up.”
It is important to note that despite those complexities, because of the urgent need for treatments for people with ALS, AMX0035 was recently conditionally approved in Canada. The FDA, the Canadian drug authority, patients, and clinicians are awaiting the results of a phase 3 trial of AMX0035, with initial results expected in 2024.
(Source: Figure 2 in “Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis,” Paganoni S., et al, Muscle & Nerve, 2021;63:31–39)
Oral edaravone was approved by the FDA based upon studies showing that it had achieved the same blood levels that were achieved with IV administration, so the clinical effectiveness data ICER reviewed was from the original approval of the IV form of the drug. In its review, ICER concluded that edaravone moderately reduces progression of ALS in people with early-stage ALS.
Studies of both AMX0035 and edaravone show that neither one has significant side effects or causes adverse reactions. And because oral edaravone doesn’t require IV administration, the complications and adverse events that can happen with intravenous administration are avoided.
From the perspectives of patients and caregivers, ICER’s clinical evaluation of these treatments falls short in several ways. For example, it doesn’t take into account that having an oral version of edaravone makes it much easier for people with ALS to use since it doesn’t require undergoing IV administration and the accompanying logistical challenges and potential adverse events. itself. This makes access to treatment more equitable for people challenged by traveling or mobility issues, including those with limited resources or who live in rural areas.
It is also important to note that because ALS progresses rapidly, the clinical value of treatments that slow its progression early on is greater because they allow people with ALS to remain more independent and require less attention from caregivers and the healthcare system. Slowing progression of the disease also gives patients additional time and opportunity to benefit from new and better treatments that may be developed. This “value of hope” is an important concept for people with ALS and should be a strong consideration for ICER and others evaluating new treatments for this disease.
In addition, wider availability of new and better treatments such as AMX0035 and oral edaravone can potentially create greater awareness among clinicians of the importance of early diagnosis of ALS. That includes clinician awareness that delays in diagnosis are particularly harmful to patients when there are multiple treatment options for slowing progression of ALS.
The interaction between the availability of new and better treatments and the actual practice of medicine (i.e., prioritization of rapid diagnosis and treatment) is often not recognized by organizations like ICER and decision makers – such as insurance companies or public health programs – who rely on their reports. Access to new treatment options has benefits beyond the direct pharmacological effectiveness of the treatment, but also can positively shift the entire clinical approach to serious and rapidly progressive illnesses like ALS.
Some aspects of new treatments that are not captured by ICER’s quantitative analysis are included in a section of the draft report called “Contextual Considerations.” This section is intended to present issues that their advisory committee should consider (see Table 5.1 below).
As is ICER’s typical practice, this report evaluates the two therapies using a variety of assumptions based upon their clinical effectiveness as it relates to changes in a person’s quality of life as measured by Quality Adjusted Life Years (QALYs). The report uses “health state utilities” based upon stages of illness. For ALS, ICER used the following “health state utilities” in its calculations:
As we have noted many times in this space, ICER’s use of QALYs and health state utilities as the basis for its economic modeling and analysis – and making implicit as well as explicit recommendations about payment, coverage, and rationing of care – is extremely problematic. That is particularly true for patients with chronic or incurable diseases like ALS. For such patients, a return to perfect health is impossible under current treatment options. By using a year in perfect health as its baseline, the QALY standard inherently undervalues any treatments developed for these types of conditions.
In the report, ICER concludes the clinical benefits of AMX0035 and edaravone are modest, which translates into lower QALYs and hence lower “cost effectiveness.” Specifically, ICER found that for both AMX0035 and edaravone, the cost per increase in QALY was very high. See the table below.
These results are based on ICER’s finding that under standard care, people with ALS had 0.89 QALYs, while with oral edaravone that increased to 0.93, and to 1.03 with AMX0035. Obviously, these treatments are not cures for ALS, but from a patient’s perspective these types of improvements are significant. For many, treatments that can slow the progression of their deterioration have very significant personal and economic value. ICER’s attempt to put a dollar amount on that value diminishes the worth of individual patients. Once again, it ignores the importance of the value of hope that better treatments will be coming in the future.
ICER’s draft report notes that, “There is tremendous need for new therapies for ALS, a disease that rapidly leads to severe disability and death in many patients. Given this context, pricing at the high end of – or even beyond – traditional cost-effectiveness ranges might be considered.” However, the report then goes on to argue that medicines such as AMX0035 should be valued less if they are approved under the FDA’s accelerated approval program, even though that process was developed specifically to benefit patients suffering from serious conditions with few available treatment options.
One aspect of ICER’s evaluation of the cost effectiveness of AMX0035 that is particularly troubling is this statement in the draft report: “TURSO [one of the two compounds in AMX0035] is the cheaper of the two components, currently available as a nutritional supplement, and is already used by some ALS patients. A pilot RCT of TURSO in 34 ALS patients found the TURSO arm had less decline in ALSFRS-R at 54 weeks. A confirmatory multicenter RCT in Italy is underway and estimated to complete in 2023.” ICER’s reference to a nutritional supplement as a possible less-expensive treatment option is very worrisome because it implies that a nutritional supplement could be as clinically beneficial as AMX0035 – and potentially be used as an economic comparator.
However, ICER’s draft report does not recognize that nutritional supplements are largely unregulated by the FDA and can vary dramatically in potency and purity. As the American Society of Health System Pharmacists wrote in 2019, “Evidence of variability in dietary supplement content has spurred efforts to standardize products. Current federal regulations regarding the manufacture of dietary supplements are not adequate.” And further, “Lax regulation of dietary supplement manufacturing presents the risk of contamination or adulteration with harmful substances, including carcinogens, and of dangerous variability in active ingredient content among products” (emphasis added). Therefore, ICER’s suggestion that a nutritional supplement – even if it is the labeled as the same active ingredient as one of the components of AMX0035 – is somehow comparable to a medicine that would be approved by the FDA (and produced under the FDA’s manufacturing rules and regulations) is irresponsible and dangerous.
Another controversial aspect of ICER’s reports about potential new treatments is their “potential budget impact” section, which assumes the U.S. healthcare system is a monolithic single payer entity. ICER’s budget impact process asserts that in any year, all new medicines should not receive more than a certain amount of money in total – regardless of how much they benefit patients. That dollar amount is based upon the average total spending on medicines in prior years divided by the average number of new treatments the FDA had approved in recent years – which is then increased by U.S. GDP +1.0% per year.
Because there are so few people in the U.S. with ALS, even though the estimated cost of AMX0035 and oral edaravone is significant ($169,000/year for AMX0035 and $171,000/year for oral edaravone), ICER’s “budget impact” calculations determined that essentially everyone with ALS could be treated with one of those two treatment options over a five-year period without exceeding ICER’s budget threshold of $734 million per year.
True enough, neither of the treatments addressed in ICER’s latest are cures for ALS. They will not eradicate the disease or return patients to perfect health. However, treatments that can extend the life of a patient or allow them to be independent for a longer period of time are of great value to those patients as well as their families and caregivers. Not surprisingly, ICER virtually ignores that perspective in its latest report. As always, the biggest problem with ICER’s analysis is not simply that is flawed discriminatory, it is that many decisionmakers – insurers, public health programs, and other payers – too often take their assessments at face value.
Our hope is that these treatments will be approved and become available to patients in short order. While we are concerned that ICER’s myopic analysis may end up limiting access to potentially life-altering therapies, PAAP is will remain focused on ensuring that the perspectives of patients – on how they value their own quality of life – is given due consideration.