Alterity Therapeutics: The race against Multiple System Atrophy

Alterity CEO David Stamler and CMO Daniel Claassen explain why multiple system atrophy is so hard to diagnose, what their drug candidate ATH434 showed in phase two, and what has to happen before a phase three trial.

Two Doctors, One Mission

David Stamler is a physician by training and has spent more than 25 years in drug development, starting in large pharmaceutical companies and moving to progressively smaller ones. He has been at Alterity for about nine years. His passion, he says, is drugs for neurological diseases, and he likes smaller companies because they are less political and things move faster, within the limits of regulation.

Daniel Claassen is a neurologist with about 18 years of practice. He trained at the Mayo Clinic, moved to the University of Virginia after his wife decided Minnesota was too cold, and has been at Vanderbilt University for 15 years, where he is a professor of neurology. He and David worked together on a Huntington’s disease program before Daniel recently joined Alterity. Asked what his role involves, he says he does whatever David wants him to do. Right now it means getting ready for the phase three study.

Treating the Disease, Not Just the Symptoms

Alterity has spent more than 20 years looking for therapies that address the underlying pathology of disease. David says symptomatic treatments matter because they improve quality of life, but in a disease like MSA they generally do not work well or do not last.

Finding a treatment that can target the underlying pathology can actually have a very big impact on people’s lives.

— David Stamler

What MSA Is

Daniel explains that MSA describes a group of diseases that used to be called “Parkinson’s, but different”. It involves the same protein that goes wrong in Parkinson’s, alpha-synuclein, but in different cells. In MSA the problem is in the supporting cells of the brain, called glia, as well as in some neurons.

The easiest way to think about it, he says, is Parkinson’s disease with more systems involved. That includes the autonomic nervous system, which controls blood pressure, bladder function, bowel function and sweating. A patient might start with trouble emptying their bladder or dizziness on standing, then develop tremor, rigidity or stumbling. They see a doctor, who suspects Parkinson’s, but the medicines do not work the way they should.

MSA is rare, and exact numbers are hard to pin down because it is hard to diagnose. David says epidemiological estimates suggest 15,000 to 20,000 patients in the US, while insurance database methods suggest 40,000 to 50,000, and the truth is probably in between. It is a distinct disease from Parkinson’s, but the key difference is the speed.

As a neurologist, you think about 6 to 10 years post-diagnosis, a patient typically dies. So it’s pretty fast.

— Daniel Claassen

Seven Doctors Before a Diagnosis

Daniel’s centre at Vanderbilt was one of the first in the US for MSA, and the older doctors there talked routinely about misdiagnosis. A large questionnaire-based study found it takes an average of seven doctors before someone is diagnosed. Simon Hinsley asked how that could change, and David quotes a former classmate: failure to consider a diagnosis is the most common reason for failure to diagnose.

Daniel says patients tend to go down two roads. Some have autonomic problems and see an autonomic specialist, while others have rigidity or gait problems and go down the movement disorder pathway. Symptoms vary widely, and one patient’s wife told them her husband’s first symptom was acting out his dreams at night. As Daniel asks, who do you see for that?

What the field needs, he says, is quantitative biomarkers, and it is closer than it was before Alterity’s phase two trial began. It will probably be a combination of:

• Neuroimaging: brain scans that look more like MSA than Parkinson’s or other rare diseases.
• Biofluid biomarkers: tests on cerebrospinal fluid or blood.
• Synuclein assays: tests that can tell MSA from Parkinson’s or other conditions.
• Clinical patterns: symptoms that behave differently from other diseases.

Daniel adds that clinicians are under pressure to see more patients in less time, so centres of excellence, clearer routes to the right specialist and clear testing protocols will all help.

Orphan Drug and Fast Track

David explains the two FDA designations. Orphan drug status is based on prevalence: if fewer than 200,000 patients in the US have a disease, a company can qualify, which brings advantages such as tax incentives to encourage development of treatments for rare conditions.

Fast track is separate. It is reserved for serious diseases, meaning debilitating or fatal, with no good treatment, and the company must show some promise, whether from preclinical studies or phase two data. Alterity has both designations.

What Phase Two Showed

Phase two read out last year, and David says it showed a very strong signal of a kind that had not been shown before in the functional impairments that occur in MSA. The company has used the data to propose a phase three study, the definitive study needed to support approval.

The key measure is part one of the MSA rating scale, which assesses activities of daily living: speech, swallowing, fine motor skills such as dressing, brushing teeth or combing hair, and walking and falling. Daniel describes seeing the data when it was unlocked. He looked before David did, and rang him up.

I called him, I was like, “Holy moly, did you look at the graph? It’s incredible.” It was really striking to see approaching 50% reduction in the rate of progression.

— Daniel Claassen

He says the existential crisis for doctors and families is that there are almost no treatments that change the course of neurodegenerative disease. A drug that slows progression could mean a patient works longer, stays upright longer and spends more time with family.

David says it is an incredible feeling because many others have tried, and to date no one has shown what Alterity has. He recalls their earlier Huntington’s drug, where the reality only sank in when someone from the commercial side told him that a thousand patients were already taking it, and he says he hopes to do the same for MSA.

Hope

Simon Hinsley met Tina, whose husband has MSA and who runs the Combat MSA foundation, before the recording, and asked what it means to be able to offer families something. David says the word is hope. MSA, like other neurodegenerative diseases, is tragic by nature. Someone is living their life, with plans and children, and it is derailed, and then a partner has to do far more caring.

Having a therapy that provides a patient hope is really important. Part of the goals for clinical trials is also to have patients and loved ones feel like they’re doing something for the future.

— Daniel Claassen

The Combat MSA relationship is just forming, David says, but the foundation is already making an impact on awareness. He sees two audiences: patients who have diverse symptoms, and physicians, who need to be aware of how widely MSA can present so they consider the diagnosis and refer patients to the right clinician.

The Road to Phase Three

David says the most immediate milestone for Alterity is agreeing the design of the phase three trial with the FDA, which was expected around the middle of the year. He told investors he does not see it as a risky meeting, but more of a confirmatory one, since the company has a very clear sense of what the next study should look like and needs the FDA’s agreement.

In the meantime, Alterity is setting up the trial, identifying vendors and laboratories, and then finding sites, where Daniel will play a key role. He lays out the timeline:

• About six months: to set up the study after FDA agreement, including the final protocol and ethics, TGA, FDA and European regulatory reviews.
• A little over a year: to enrol the roughly 200 patients the company is targeting.
• Another year: for the last patient to complete 12 months of treatment.
• About three months: to clean and lock the database and generate the data.

That adds up to about two and a quarter to two and a half years, though he notes that delays can happen. One practical advantage is that ATH434 is an oral tablet, not an injectable.

Beyond MSA

David calls ATH434 an amazing drug because it may help in other neurodegenerative diseases. Parkinson’s disease shares pathology with MSA, and Alterity has been pursuing patent strategies to make that feasible. He also points to Friedreich’s ataxia, another orphan disease involving an imbalance of iron, which is how ATH434 works. The company has other drugs in its patent portfolio that could move into the clinic, and is entertaining licensing opportunities.

On how a phase three trial might be supported, David says there has been tremendous inbound interest in the program from large and mid-sized pharmaceutical companies, given the unmet need and the orphan status, and Alterity is actively looking at it.

What 2030 Could Look Like

Simon Hinsley finished by asking Daniel what changes in the clinic if ATH434 succeeds in phase three and reaches patients. Daniel’s answer is that he would have something in his armamentarium that can help, which he does not today.

It completely changes the dialogue. You’re diagnosed with MSA, now we’re gonna give you this medication, and here’s what we’re hoping to see. It changes the narrative.

— Daniel Claassen

He thinks it would probably speed up diagnosis, because getting a diagnosis would suddenly matter, and would change how clinics are set up, as happens whenever a new treatment is approved. It goes back, he says, to hope.

This post summarises a conversation and is not medical or investment advice. ATH434 is an investigational drug and has not been approved by any regulator, and results from earlier trials do not guarantee future outcomes.